Einar M Sigurdsson, Ph.D.

Targeting hyperphosphorylated tau protein with a monoclonal antibodyat an advanced stage of tau pathology improves cognition in a mouse model
Boutajangout A.; Sait H.B.R.; Gonzalez V.; Sigurdsson E.
2011 ;7(4 SUPPL 1):S480-S481, Alzheimer's & Dementia
Background: Immunotherapy targeting pathological tau is emerging as a promising approach to treat tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia. We have previously shown that prophylactic active or passive tau immunotherapy, starting at 2-3 months of age, clears tau pathology and improves function (Asuni A. et al., J. Neurosci. 2007, Boutajangout A. et al., J. Neurosci. 2010, Boutajangout A. et al., ICAD 2010). Here we assessed if a phospho-specific monoclonal, 4E6G7, targeting the same epitope, would be efficacious if treatment commenced at an advanced stage of tau pathology (8-9 months). Methods: htau/PS1 mice without mouse tau protein (8-9 months) were injected intraperitoneally (250 mg/125 ml) once per week with a novel phospho- specific tau monoclonal, 4E6G7 (n = 9) or pooled mouse IgG (n = 10) for a total of 13 injections. Their behavior was analyzed at 11-12 months of age and brain tissue subsequently harvested for analyses of treatment efficacy. Results: The immunized mice (n = 7-8) performed substantially better than controls (n = 6) on the Radial Arm Maze (p < 0.0001; post hoc, p < 0.01-0.001 on days 2, 3, 5-9), the Closed Field Symmetrical Maze with 35-69% fewer errors in simple, intermediate and complex tasks (p < 0.05-0.003), and the Object Recognition Task (63% time spent with a novel object vs. 46% for controls, p < 0.05). The groups did not differ in various sensorimotor tasks, indicating that the robust cognitive improvements cannot be explained by sensorimotor effects, which further strengthens our results. Interestingly, more controls died during the study (40%) than immunized mice (22%), providing an additional support for the beneficial effect of the monoclonal tau antibody. Histological and biochemical analyses are underway. Conclusions: These results indicate pronounced efficacy of passive tau immunotherapy at an advanced stage of tauopathy, which suggests that this approach may be beneficial after clinical onset of AD and other tauopathies
— id: 136965, year: 2011, vol: 7, page: S480, stat: Journal Article,

Tau as a therapeutic target for Alzheimer's disease
Boutajangout, A; Sigurdsson, E M; Krishnamurthy, P K
2011 Sep 1;8(6):666-677, Current Alzheimer research
Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer's disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained
— id: 147678, year: 2011, vol: 8, page: 666, stat: Journal Article,

Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain
Boutajangout, Allal; Ingadottir, Johanna; Davies, Peter; Sigurdsson, Einar M
2011 Aug;118(4):658-667, Journal of neurochemistry
J. Neurochem. (2011) 118, 658-667. ABSTRACT: Targeting hyperphosphorylated tau by immunotherapy is emerging as a promising approach to treat tauopathies such as Alzheimer's disease and frontotemporal dementia. We have previously reported that active tau immunization clears tau aggregates from the brain and attenuates or prevents functional impairments in two different tangle mouse models. Here, we assessed the efficacy of passive immunization with the PHF1 antibody, which targets a phospho-epitope within one of our active immunogens. Homozygous female tangle mice (JNPL3, 2-3 months) were injected intraperitoneally once per week with PHF1 or pooled mouse IgG (250 mug/125 muL; n = 10 per group) for a total of 13 injections. Their behavior was assessed at 5-6 months of age and brain tissue was subsequently harvested for analyses of treatment efficacy. The treated mice performed better than controls on the traverse beam task (p < 0.03), and had 58% less tau pathology in the dentate gyrus of the hippocampus (p = 0.02). As assessed by western blots, the antibody therapy reduced the levels of insoluble pathological tau by 14-27% (PHF1, p < 0.05; PHF1/total tau, p < 0.0001) and 34-45% (CP13 or CP13/total tau, p < 0.05). Levels of soluble tau and sarkosyl soluble tau were unchanged, compared with controls, as well as total tau levels in all the fractions. Plasma levels of PHF1 correlated inversely with tau pathology in the brainstem (p < 0.01), with a strong trend in the motor cortex (p < 0.06) as well as with insoluble total tau levels (p < 0.02), indicating that higher dose of antibodies may have a greater therapeutic effect. Significant correlation was also observed between performance on the traverse beam task and PHF1 immunoreactivity in the dentate gyrus (p < 0.05) as well as with insoluble PHF1/total tau ratio on western blots (p < 0.04). These results show that passive immunization with tau antibodies can decrease tau pathology and functional impairments in the JNPL3 model. Future studies will determine the feasibility of this approach with other monoclonals and in different tangle models in which thorough cognitive assessment can be performed
— id: 135543, year: 2011, vol: 118, page: 658, stat: Journal Article,

Immunotherapy for tauopathies
Gu, Jiaping; Sigurdsson, Einar M
2011 Nov;45(3):690-695, Journal of molecular neuroscience
Pathological tau protein is found in Alzheimer's disease and related tauopathies. The protein is hyperphosphorylated and/or mutated which leads to aggregation and neurotoxicity. Because cognitive functions correlate well with the degree of tau pathology, clearing these aggregates is a promising therapeutic approach. Studies pioneered by our laboratory and confirmed by others have shown that both active and passive immunizations targeting disease-related tau epitopes successfully reduce tau aggregates in vivo and slow or prevent behavioral impairments in mouse models of tauopathy. Here, we summarize recent advances in this new field
— id: 140523, year: 2011, vol: 45, page: 690, stat: Journal Article,

In vivo follow up of cerebral aging and side effects of anti-amyloid immunotherapies in the mouse lemur primate
Joseph-Mathurin N.; Dorieux O.; Kraska A.; Santin M.; Trouche S.; Boutajangout A.; Hantraye P.; Verdier J.-M.; Sigurdsson E.; Mestre-Frances N.; Dhenain M.
2011 ;7(4 SUPPL 1):S44-S44, Alzheimer's & Dementia
Background: Active anti-amyloid immunotherapy is a strategy developed against Alzheimer's disease.ApproacheswithAs1-42 orK6As1-30 immunogens in an adjuvant decrease amyloid-s burden and prevent cognitive decline in transgenic mice (Asuni et al, 2006). However, clinical trials of As1-42 immunotherapy have induced side effects like encephalitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). Mouse lemurs can develop As plaques with age (Mestre-Frances et al, 2000). Such a primate modelmay bemore predictive than rodents of human side effects.We studied, by magnetic resonance imaging (MRI), immunotherapies in these primates. Methods: A first cohort was used to compare K6As1-30 (n = 4; 5.8 +/- 0.2 years) and As1-42 (n = 4; 5.9 +/- 0.2 years) immunogens in alum adjuvant. Asecond cohortwas used to evaluateK6As1-30 (n=6; 4.660.2 years) compared to adjuvant alone (n = 6; 4.7 +/- 0.3 years). All the animals were followed- up by MRI (7T PharmaScan-Bruker) to evaluate neuroinflammation, microhemorrhages and other forms of iron deposition, with T2-weighted and T2*-weighted sequences (resolution=(234x234x234)mm³). The hypointense regions from T2*-weighted images were quantified and evaluate by histology. A complementary study of age effectwas performedwith twenty other naive animals (1.5 to 4.9 years). Results: The T2-weighted images did not show any neuroinflammation during immunization, irrespective of the immunogen. Microhemorrhages were detected in the cerebral parenchyma at the histological analysis of the first cohort. The animals treated with K6As1-30 presented less microhemorrhages compared to those treated with As1-42 vaccine (Mann-Whitney, p < 0.05). These small microhemorrhages were not detected on the T2*-weighted images. However hypointense signalwas detected on MRI and corresponded to iron deposits in the choroid plexus. Its volume increasedwith natural aging (r= 0.60; p< 0.001) and withAs1-42 compared to K6As1-30 treatment (ANOVA, p < 0.05). No difference was detected between K6As1-30 and adjuvant alone. Conclusions: The immunotherapies studied in the mouse lemur primate did not lead to any MRI sign of neuroinflammation. The K6As1-30 strategy appears to be safer than theAs1-42 strategy as it provokes less microhemorrhages in the cerebral parenchyma and less iron deposits in the choroid plexus
— id: 136974, year: 2011, vol: 7, page: S44, stat: Journal Article,

In vivo follow-up of cerebral aging and side effects of anti-amyloid immunotherapies in the mouse lemur primate
Joseph-Mathurin N.; Dorieux O.; Kraska A.; Santin M.; Trouche S.; Boutajangout A.; Hantraye P.; Verdier J.-M.; Sigurdsson E.; Mestre-Frances N.; Dhenain M.
2011 ;7(4 SUPPL 1):S462-S463, Alzheimer's & Dementia
Background: Active anti-amyloid immunotherapy is a strategy developed againstAlzheimer's disease.ApproacheswithAs1-42 orK6As1-30 immunogens in an adjuvant decrease amyloid-s burden and prevent cognitive decline in transgenic mice (Asuni et al, 2006). However, clinical trials of As1-42 immunotherapy have induced side effects like encephalitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). Mouse lemurs can develop As plaques with age (Mestre-Frances et al, 2000). Such a primate modelmay be more predictive than rodents of human side effects.We studied, by magnetic resonance imaging (MRI), immunotherapies in these primates. Methods: A first cohort was used to compare K6As1-30 (n = 4; 5.8 6 0.2years) and As1-42 (n = 4; 5.96 0.2years) immunogens in alumadjuvant. Asecond cohortwas used to evaluate K6As1-30 (n=6; 4.660.2years) compared to adjuvant alone (n = 6; 4.7 6 0.3years). All the animals were followed- up by MRI (7T PharmaScan-Bruker) to evaluate neuroinflammation, microhemorrhages and other forms of iron deposition, with T2-weighted and T2*-weighted sequences (resolution = (234x234x234)Amm3). The hypointense regions from T2*-weighted images were quantified and evaluate by histology. A complementary study of age effect was performed with twenty other naive animals (1.5 to 4.9years). Results: TheT2-weighted images did not show any neuroinflammation during immunization, irrespective of the immunogen. Microhemorrhages were detected in the cerebral parenchyma at the histological analysis of the first cohort. The animals treated with K6As1-30 presented less microhemorrhages compared to those treated with As1-42 vaccine (Mann-Whitney, p < 0.05). These small microhemorrhages were not detected on the T2*-weighted images. However hypointense signal was detected onMRI and corresponded to iron deposits in the choroid plexus. Its volume increased with natural aging (r=0.60; p<0.001) and with As1-42 compared toK6As1-30 treatment (ANOVA, p<0.05).No difference was detected between K6As1-30 and adjuvant alone. Conclusions: The immunotherapies studied in the mouse lemur primate did not lead to any MRI sign of neuroinflammation. The K6As1-30 strategy appears to be safer than the As1-42 strategy as it provokes less microhemorrhages in the cerebral parenchyma and less iron deposits in the choroid plexus
— id: 136967, year: 2011, vol: 7, page: S462, stat: Journal Article,

Immunization with a pseudophosphorylated tau epitope clears tau pathology in a mouse model
Krishnamurthy P.; Gonzalez V.; Rajamohamedsait H.B.; Sigurdsson E.
2011 ;7(4 SUPPL 1):S481-S482, Alzheimer's & Dementia
Background: Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders. Recent studies from our group have shown that immunization with an AD specific phospho-tau immunogen Tau379-408[P-Ser396,404] alleviates brain levels of aggregated tau and slows the progression of motor deficits or prevents cognitive impairments in two different tangle models (Asuni A. et al. J. Neurosci., 2007, Boutajangout A. et al., J. Neurosci., 2010). To assess potential epitope specificity and safety of this promising therapeutic effect, we are examining several tau epitopes. Here we assessed the efficacy of using a pseudo-phosphorylated tau immunogen. Methods: Homozygous JNPL3 mice were immunized with Tau379-408[ESer396, E-Ser404] in alum adjuvant (n = 13) or with adjuvant only (n = 7), starting at 2 months. Mice were tested on various sensorimotor tasks (rotarod, traverse beam, locomotor activity and grip strength) at 5 and 8 months of age. Antibody titers were determined and at 8 months their brains were processed for tau biochemistry and histology. Results: The vaccine elicited a robust antibody response towards the immunogen, and its phosphorylated and non-phosphorylated analogs. Which is as expected since this region of the tau protein is highly immunogenic. The immunized mice had a 24% reduction in soluble PHF1/total tau ratio on western blots (p = 0.04), and a 42% reduction in PHF1 immunostaining in the dentate gyrus (p < 0.03), compared to alum-treated mice. Levels of sarkosyl insoluble human and total tau were highly variable in both groups and not significantly different. Biochemical and histological analyses with other antibodies and of other brain regions is underway. Disappointingly, potential improvements in motor function of the immunized mice could not be assessed since the animals did not develop overt signs of such impairments at the ages tested, in contrast to our previous observation in the same homozygous model (Asuni A. et al., J. Neurosci., 2007). Unfortunately, such changes in phenotype are commonly observed in transgenic mice. Conclusions: These findings indicate that immunological targeting using a pseudo-phosphorylated tau epitope can reduce pathological tau within the brain, further supporting the feasibility of tau immunotherapy
— id: 136964, year: 2011, vol: 7, page: S481, stat: Journal Article,

Therapeutic Applications of Antibodies - Antibodies in Non-Infectious Neurodegenerative Diseases
Krishnamurthy PK; Sigurdsson EM
2011 Sep;28(5):511-517, New biotechnology
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS) are all characterized histologically by the presence of deposits of misfolded proteins, tau and amyloid, -synuclein, huntingtin or superoxide dismutase respectively. Currently these illnesses do not have any disease modifying treatment options. A novel therapeutic strategy that is being pursued is immunomodulation, which is using the body's immune system to target the self proteins that are deposited. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase III clinical trials. As new insights are gained, it is hoped that these immunotherapies will be effective tools at slowing the progression of these debilitating diseases
— id: 130411, year: 2011, vol: 28, page: 511, stat: Journal Article,

Mechanistic Studies of Antibody-Mediated Clearance of Tau Aggregates Using an ex vivo Brain Slice Model
Krishnamurthy, Pavan K; Deng, Yan; Sigurdsson, Einar M
2011 ;2:59-59, Frontiers in psychiatry
Recent studies have shown that immunotherapy clears amyloid beta (Abeta) plaques and reduces Abeta levels in mouse models of Alzheimer's disease (AD), as well as in AD patients. Tangle pathology is also relevant for the neurodegeneration in AD, and our studies have shown that active immunization with an AD related phospho-tau peptide reduces aggregated tau within the brain and slows the progression of tauopathy-induced behavioral impairments. Thus, clearance of neurofibrillary tangles and/or their precursors may reduce synaptic and neuronal loss associated with AD and other tauopathies. So far the mechanisms involved in antibody-mediated clearance of tau pathology are yet to be elucidated. In this study we have used a mouse brain slice model to examine the uptake and localization of FITC labeled anti-tau antibodies. Confocal microscopy analysis showed that the FITC labeled anti-tau antibody co-stained with phosphorylated tau, had a perinuclear appearance and co-localized with markers of the endosomal/lysosomal pathway. Additionally, tau and FITC-IgG were found together in an enriched lysosome fraction. In summary, antibody-mediated clearance of intracellular tau aggregates appears to occur via the lysosomal pathway
— id: 139751, year: 2011, vol: 2, page: 59, stat: Journal Article,

Postsynaptic degeneration as revealed by PSD-95 reduction occurs after advanced A beta and tau pathology in transgenic mouse models of Alzheimer's disease
Shao, Charles Y.; Mirra, Suzanne S.; Sait, Hameetha B. R.; Sacktor, Todd C.; Sigurdsson, Einar M.
2011 SEP ;122(3):285-292, Acta neuropathologica
Impairment of synaptic plasticity underlies memory dysfunction in Alzheimer's disease (AD). Molecules involved in this plasticity such as PSD-95, a major postsynaptic scaffold protein at excitatory synapses, may play an important role in AD pathogenesis. We examined the distribution of PSD-95 in transgenic mice of amyloidopathy (5XFAD) and tauopathy (JNPL3) as well as in AD brains using double-labeling immunofluorescence and confocal microscopy. In wild type control mice, PSD-95 primarily labeled neuropil with distinct distribution in hippocampal apical dendrites. In 3-month-old 5XFAD mice, PSD-95 distribution was similar to that of wild type mice despite significant A beta deposition. However, in 6-month-old 5XFAD mice, PSD-95 immunoreactivity in apical dendrites markedly decreased and prominent immunoreactivity was noted in neuronal soma in CA1 neurons. Similarly, PSD-95 immunoreactivity disappeared from apical dendrites and accumulated in neuronal soma in 14-month-old, but not in 3-month-old, JNPL3 mice. In AD brains, PSD-95 accumulated in Hirano bodies in hippocampal neurons. Our findings support the notion that either A beta or tau can induce reduction of PSD-95 in excitatory synapses in hippocampus. Furthermore, this PSD-95 reduction is not an early event but occurs as the pathologies advance. Thus, the time-dependent PSD-95 reduction from synapses and accumulation in neuronal soma in transgenic mice and Hirano bodies in AD may mark postsynaptic degeneration that underlies long-term functional deficits
— id: 137812, year: 2011, vol: 122, page: 285, stat: Journal Article,

Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model
Boutajangout, Allal; Quartermain, David; Sigurdsson, Einar M
2010 Dec 8;30(49):16559-16566, Journal of neuroscience
Harnessing the immune system to clear protein aggregates is emerging as a promising approach to treat various neurodegenerative diseases. In Alzheimer's disease (AD), several clinical trials are ongoing using active and passive immunotherapy targeting the amyloid-beta (Abeta) peptide. Limited emphasis has been put into clearing tau/tangle pathology, another major hallmark of the disease. Recent findings from the first Abeta vaccination trial suggest that this approach has limited effect on tau pathology and that Abeta plaque clearance may not halt or slow the progression of dementia in individuals with mild-to-moderate AD. To assess within a reasonable timeframe whether targeting tau pathology with immunotherapy could prevent cognitive decline, we developed a new model with accelerated tangle development. It was generated by crossing available strains that express all six human tau isoforms and the M146L presenilin mutation. Here, we show that this unique approach completely prevents severe cognitive impairment in three different tests. This remarkable effect correlated well with extensive clearance of abnormal tau within the brain. Overall, our findings indicate that immunotherapy targeting pathological tau is very feasible for tauopathies, and should be assessed in clinical trials in the near future
— id: 115432, year: 2010, vol: 30, page: 16559, stat: Journal Article,

Alzheimer's disease: challenges ahead
Sigurdsson, Einar M
2010 ;1:5-5, Frontiers in psychiatry
— id: 128803, year: 2010, vol: 1, page: 5, stat: Journal Article,

Murine models of Alzheimer's disease and their use in developing immunotherapies
Wisniewski, Thomas; Sigurdsson, Einar M
2010 Oct;1802(10):847-859, Biochimica & biophysica acta
Alzheimer's disease (AD) is one of the categories of neurodegenerative diseases characterized by a conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In AD, the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. An additional important feature of AD is the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror specific aspects of AD pathology. None of the current murine models is a perfect match of the human disease. Perhaps the most exciting of the therapeutic approaches being developed is immunomodulation targeting the aggregating proteins, Abeta and tau. This type of AD therapy is currently being assessed in many transgenic mouse models, and promising findings have led to clinical trials. However, there is a discrepancy between results in murine models and ongoing clinical trials, which highlight the limitations of these models and also of our understanding of the underlying etiology and pathogenesis of AD. Because of these uncertainties, Tg models for AD are continuously being refined with the aim to better understand the disease and to enhance the predictive validity of potential treatments such as immunotherapies
— id: 112199, year: 2010, vol: 1802, page: 847, stat: Journal Article,

Diminished Amyloid-beta Burden in Tg2576 Mice Following a Prophylactic Oral Immunization with a Salmonella-Based Amyloid-beta Derivative Vaccine
Boutajangout, Allal; Goni, Fernando; Knudsen, Elin; Schreiber, Fernanda; Asuni, Ayodeji; Quartermain, David; Frangione, Blas; Chabalgoity, Alejandro; Wisniewski, Thomas; Sigurdsson, Einar M
2009 Jan 1;18(4):961-972, Journal of Alzheimer's Disease
Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/Wyeth AD vaccine trial, we proposed using amyloid-beta (Abeta) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3-5 months of age with a Salmonella vaccine expressing K6Abeta<formula> _{1-30}</formula>. At 22-24 months of age, cortical Abeta plaque burden and total Abeta<formula>_{40}</formula>/<formula>_{42}</formula> levels were reduced by 48-75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Abeta antibody studies. These results further support our findings with this immunogen delivered subcutaneously and demonstrate its efficacy when given orally which may provide added benefits for human use
— id: 107413, year: 2009, vol: 18, page: 961, stat: Journal Article,

Synthetic immunogenic but non-deposit-forming polypeptides and peptides homologous to amyloid beta, prion protein, amylin, alpha-synuclein, or polyglutamine repeats for induction of an immune response thereto
Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2009 ;27(7):957-964, Official gazette of the United States Patent & Trademark Office. Patents
The present invention relates to immunogenic but non-depositing-forming polypeptides or peptides homologous to amyloid beta, prion, amylin or alpha-synuclein which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid beta peptides and amyloid deposits, to prion protein and prion deposits, to amylin and amylin deposits, to alpha-synuclein and deposits containing alpha-synuclein, or to polyglutamine repeats and deposits of proteins containing polyglutamine repeats. Described are also antibodies directed against such peptides, their generation, and their use in methods of passive immunization to such peptides and deposits
— id: 97983, year: 2009, vol: 27, page: 957, stat: Journal Article,

Tau-focused immunotherapy for Alzheimer's disease and related tauopathies
Sigurdsson, Einar M
2009 Oct;6(5):446-450, Current Alzheimer research
Immunotherapies targeting the amyloid-beta (Abeta) peptide in Alzheimer's disease (AD) have consistently been effective in mouse studies and shown promise in clinical trials, although some setbacks have occurred. First, encephalitis was observed in a small subset of patients. More recent autopsy data from a few subjects suggests that clearance of Abeta plaques may not halt cognitive deterioration once impairments are evident, emphasizing the need for other more effective approaches at that stage of the disease. Another important target in AD is the neurofibrillary tangles and its precursors, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As Abeta and tau pathologies are likely synergistic, targeting both together may be more effective, and perhaps essential as early diagnosis prior to cognitive decline is currently unavailable. Also, Abeta immunotherapy results in a very limited indirect clearance of tau aggregates, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that active immunization targeting an AD phospho-tau epitope reduces aggregated tau in the brain and prevents/slows progression of the tangle-related behavioral phenotype, including cognitive impairment. These antibodies enter the brain and bind to pathological tau within neurons although the therapeutic effect may at least in part be due to clearance of extracellular tau that may have biological effects. We are currently clarifying the mechanism of these promising findings, determining its epitope specificity as well as assessing the feasibility of this approach for clinical trials
— id: 105174, year: 2009, vol: 6, page: 446, stat: Journal Article,

Antibody response and plasma Abeta1-40 levels in young Microcebus murinus primates immunized with Abeta1-42 and its derivatives
Trouche, Stephanie G; Asuni, Ayodeji; Rouland, Sylvie; Wisniewski, Thomas; Frangione, Blas; Verdier, Jean-Michel; Sigurdsson, Einar M; Mestre-Frances, Nadine
2009 Feb 11;27(7):957-964, Vaccine
We have been developing Abeta derivative vaccines with the objective to improve the safety of Abeta targeting immunotherapy. Our Abeta homologs are designed to have less direct toxicity and to produce a modified immune response compared to Abeta. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n=25) that with age develop Abeta plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-Abeta IgM response. Abeta1-42, K6Abeta1-30 and K6Abeta1-30[E(18)E(19)] resulted in a high anti-Abeta IgG response, whereas Abeta1-30[E(18)E(19)] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas Abeta1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Abeta1-40 often correlated with increase in Abeta1-40 in plasma, which suggests that the antibodies were binding to Abeta in vivo. Interestingly, significant transient weight gain was observed (K6Abeta1-30-, Abeta1-30[E(18)E(19)]- and Abeta1-42-treated) or a trend in the same direction (K6Abeta1-30[E(18)E(19)]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Abeta1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Abeta derivatives. Our present findings indicate that most of our Abeta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach
— id: 91348, year: 2009, vol: 27, page: 957, stat: Journal Article,

Synthetic immunogenic but non amyloidogenic peptides homologous to amyloid beta for induction of an immune response to amyloid beta and amyloid deposits
Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2008 ;27(7):957-964, Official gazette of the United States Patent & Trademark Office. Patents
The present invention relates to synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid beta peptides and amyloid deposits
— id: 97982, year: 2008, vol: 27, page: 957, stat: Journal Article,

High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice
Goni, F; Prelli, F; Schreiber, F; Scholtzova, H; Chung, E; Kascsak, R; Brown, D R; Sigurdsson, E M; Chabalgoity, J A; Wisniewski, T
2008 May 15;153(3):679-686, Neuroscience
Significant outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (C for cellular), to a toxic and infectious form, PrP(Sc) (Sc for scrapie). None of the prionoses currently have an effective treatment. Some forms of prion disease are thought to be spread by oral ingestion of PrP(Sc), such as chronic wasting disease and variant Creutzfeldt-Jakob disease. Attempts to obtain an active immunization in wild-type animals have been hampered by auto-tolerance to PrP and potential toxicity. Previously, we demonstrated that it is possible to overcome tolerance and obtain a specific anti-PrP antibody response by oral inoculation of the PrP protein expressed in an attenuated Salmonella vector. This past study showed that 30% of vaccinated animals were free of disease more than 350 days post-challenge. In the current study we have both optimized the vaccination protocol and divided the vaccinated mice into low and high immune responder groups prior to oral challenge with PrP(Sc) scrapie strain 139A. These methodological refinements led to a significantly improved therapeutic response. 100% of mice with a high mucosal anti-PrP titer immunoglobulin (Ig) A and a high systemic IgG titer, prior to challenge, remained without symptoms of PrP infection at 400 days (log-rank test P<0.0001 versus sham controls). The brains from these surviving clinically asymptomatic mice were free of PrP(Sc) infection by Western blot and histological examination. These promising findings suggest that effective mucosal vaccination is a feasible and useful method for overcoming tolerance to PrP and preventing prion infection via an oral route
— id: 99013, year: 2008, vol: 153, page: 679, stat: Journal Article,

Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging
Scholtzova, Henrieta; Wadghiri, Youssef Z; Douadi, Moustafa; Sigurdsson, Einar M; Li, Yong-Sheng; Quartermain, David; Banerjee, Pradeep; Wisniewski, Thomas
2008 Sep;86(12):2784-2791, Journal of neuroscience research
Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to improve learning and memory in several preclinical models of Alzheimer's disease (AD). Memantine has also been shown to reduce the levels of amyloid beta (Abeta) peptides in human neuroblastoma cells as well as to inhibit Abeta oligomer-induced synaptic loss. In this study, we assessed whether NMDA receptor inhibition by memantine in transgenic mice expressing human amyloid-beta precursor protein (APP) and presenilin 1 (PS1) is associated with cognitive benefit and amyloid burden reduction by using object recognition, micromagnetic resonance imaging (muMRI), and histology. APP/PS1 Tg mice were treated either with memantine or with vehicle for a period of 4 months starting at 3 months of age. After treatment, the mice were subjected to an object recognition test and analyzed by ex vivo muMRI, and histological examination of amyloid burden. muMRI was performed following injection with gadolinium-DTPA-Abeta(1-40). We found that memantine-treated Tg mice performed the same as wild-type control mice, whereas the performance of vehicle-treated Tg mice was significantly impaired (P = 0.0081, one-way ANOVA). Compared with vehicle-treated animals, memantine-treated Tg mice had a reduced plaque burden, as determined both histologically and by muMRI. This reduction in amyloid burden correlates with an improvement in cognitive performance. Thus, our findings provide further evidence of the potential role of NMDA receptor antagonists in ameliorating AD-related pathology. In addition, our study shows, for the first time, the utility of muMRI in conjunction with gadolinium-labeled Abeta labeling agents to monitor the therapeutic response to amyloid-reducing agents. (c) 2008 Wiley-Liss, Inc
— id: 79463, year: 2008, vol: 86, page: 2784, stat: Journal Article,

Immunotherapy targeting pathological tau protein in Alzheimer's disease and related tauopathies
Sigurdsson, Einar M
2008 Nov;15(2):157-168, Journal of Alzheimer's Disease
Immunotherapies that target the amyloid-beta (Abeta) peptide in Alzheimer's disease (AD) have shown promise in animal and human studies. Although the first clinical trial was halted because of adverse reactions, this approach has been refined and additional trials are underway. Another important target in AD is the neurofibrillary tangles, composed primarily of hyperphosphorylated tau proteins, which correlate well with the degree of dementia. As Abeta and tau pathologies are likely synergistic, targeting both should be more effective and may be essential as early diagnosis prior to cognitive decline is currently not available. Also, Abeta immunotherapy only results in a very limited indirect clearance of tau aggregates in dystrophic neurites, showing the importance of developing a separate therapy that directly targets pathological tau. Our findings in two tangle mouse models indicate that immunization with a phospho-tau derivative reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. These antibodies enter the brain and bind to pathological tau within neurons. We are currently clarifying further the mechanism of action of this promising therapeutic approach and determining its epitope specificity
— id: 90050, year: 2008, vol: 15, page: 157, stat: Journal Article,

A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice
Sigurdsson, Einar M; Wadghiri, Youssef Z; Mosconi, Lisa; Blind, Jeffrey A; Knudsen, Elin; Asuni, Ayodeji; Scholtzova, Henrieta; Tsui, Wai H; Li, Yongsheng; Sadowski, Martin; Turnbull, Daniel H; de Leon, Mony J; Wisniewski, Thomas
2008 Jun;29(6):836-847, Neurobiology of aging
Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6Abeta1-30, which is homologous to Abeta, and allows plaque detection in vivo. muMRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6Abeta1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2(*)-weighted sequence was used to provide 100mum isotropic resolution with imaging times of 115min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6Abeta1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p</=0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models
— id: 71031, year: 2008, vol: 29, page: 836, stat: Journal Article,

Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements
Asuni, Ayodeji A; Boutajangout, Allal; Quartermain, David; Sigurdsson, Einar M
2007 Aug 22;27(34):9115-9129, Journal of neuroscience
Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia
— id: 73919, year: 2007, vol: 27, page: 9115, stat: Journal Article,

Mucosal vaccination can prevent prion infection via an oral route
Wisniewski, T; Prelli, F; Scholtzova, H; Wu, H; Chung, E; Chabalgoity, JA; Sigurdsson, E; Sadowski, M; Goni, F
2007 ;68(12):A348-A348, Neurology
— id: 97602, year: 2007, vol: 68, page: A348, stat: Journal Article,

Therapeutic approaches for prion and Alzheimer's diseases
Wisniewski, Thomas; Sigurdsson, Einar M
2007 Aug;274(15):3784-3798, FEBS journal
Alzheimer's and prion diseases belong to a category of conformational neurodegenerative disorders [Prusiner SB (2001) N Eng J Med344, 1516-1526; Sadowski M & Wisniewski T (2007) Curr Pharm Des 13, 1943-1954; Beekes M (2007) FEBS J 274, 575]. Treatments capable of arresting or at least effectively modifying the course of disease do not yet exist for either one of these diseases. Alzheimer's disease is the major cause of dementia in the elderly and has become an ever greater problem with the aging of Western societies. Unlike Alzheimer's disease, prion diseases are relatively rare. Each year only approximately 300 people in the USA and approximately 100 people in the UK succumb to various forms of prion diseases [Beekes M (2007) FEBS J 274, 575; Sigurdsson EM & Wisniewski T (2005) Exp Rev Vaccines 4, 607-610]. Nevertheless, these disorders have received great scientific and public interest due to the fact that they can be transmissible among humans and in certain conditions from animals to humans. The emergence of variant Creutzfeld-Jakob disease demonstrated the transmissibility of the bovine spongiform encephalopathy to humans [Beekes M (2007) FEBS J 274, 575]. Therefore, the spread of bovine spongiform encephalopathy across Europe and the recently identified cases in North America have put a large human population at risk of prion infection. It is estimated that at least several thousand Britons are asymptomatic carriers of prion infections and may develop variant Creutzfeld-Jakob disease in the future [Hilton DA (2006) J Pathol 208, 134-141]. This delayed emergence of human cases following the near elimination of bovine spongiform encephalopathy in the UK may occur because prion disease have a very prolonged incubation period, ranging from months to decades, which depends on the amount of inoculum, the route of infection and the genetic predisposition of the infected subject [Hilton DA (2006) J Pathol 208, 134-141]. Therefore, there is a great need for effective therapies for both Alzheimer's disease and prion diseases.
— id: 73006, year: 2007, vol: 274, page: 3784, stat: Journal Article,

Vaccination of Alzheimer's model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages
Asuni, Ayodeji A; Boutajangout, Allal; Scholtzova, Henrieta; Knudsen, Elin; Li, Yong Sheng; Quartermain, David; Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2006 Nov;24(9):2530-2542, European journal of neuroscience
Abstract Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (Abeta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Abeta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Abeta burden, Abeta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Abeta deposit burden by 31% and Abeta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Abeta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Abeta burden, did not increase cerebral bleeding or vascular Abeta deposits in contrast to several Abeta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Abeta burden when used with an adjuvant suitable for humans, without increasing vascular Abeta deposits or microhemorrhages
— id: 69181, year: 2006, vol: 24, page: 2530, stat: Journal Article,

Plaque-associated overexpression of insulin-degrading enzyme in the cerebral cortex of aged transgenic tg2576 mice with Alzheimer pathology
Leal, Maria C; Dorfman, Veronica B; Gamba, Agata Fernandez; Frangione, Blas; Wisniewski, Thomas; Castano, Eduardo M; Sigurdsson, Einar M; Morelli, Laura
2006 Oct;65(10):976-987, Journal of neuropathology & experimental neurology
It was proposed that insulin-degrading enzyme (IDE) participates in the clearance of amyloid beta (Abeta) in the brain, and its low expression or activity may be relevant for the progression of Alzheimer disease. We performed a longitudinal study of brain level, activity, and distribution of IDE in transgenic mice (Tg2576) expressing the Swedish mutation in human Abeta precursor protein. At 16 months of age, Tg2576 showed a significant 2-fold increment in IDE protein level as compared with 4.5- and 11-month-old animals. The peak of IDE was in synchrony with the sharp accumulation of sodium dodecyl sulfate-soluble Abeta and massive Abeta deposition into plaques. At this stage, IDE appeared surrounding Abeta fibrillar deposits within glial fibrillar acidic protein-positive astrocytes, suggesting that it was locally overexpressed during the Abeta-mediated inflammation process. When primary astrocytes were exposed to fibrillar Abeta in vitro, IDE protein level increased as compared with control, and this effect was reduced by the addition of U0126, a specific inhibitor of the ERK1/2 mitogen-activated protein kinase cascade. We propose that in Tg2576 mice and in contrast to its behavior in Alzheimer brains, active IDE increases with age around plaques as a component of astrocyte activation as a result of Abeta-triggered inflammation
— id: 68945, year: 2006, vol: 65, page: 976, stat: Journal Article,

Assessing the effects of memantine in APP/PS1 transgenic mice by behavioural studies and ex vivo imaging of amyloid plaques using gadolinium labelled amyloid beta peptides and mu MRI
Scholtzova, H; Wadghiri, YZ; Sigurdsson, EM; Douadi, M; Li, Y; Quartermain, D; Banerjee, PK; Wisniewski, T
2006 SEP ;16(11):S483-S483, European neuropsychopharmacology
— id: 69190, year: 2006, vol: 16, page: S483, stat: Journal Article,

Immunotherapy for conformational diseases
Sigurdsson, Einar M
2006 ;12(20):2569-2585, Current pharmaceutical design
The seminal finding that immunization with amyloid-beta 1-42 in Alzheimer's disease (AD) mouse model prevented formation of and/or cleared amyloid plaques has led to numerous studies exploring related approaches for AD and other conformational degenerative disorders. While clinical trials in AD patients were discouraging because of serious side effects, this approach remains promising in light of recent findings in animal models, in which refinements aimed at reducing potential adverse reactions continue to lead to cognitive improvements. In addition to AD and its models, this type of therapy has primarily been assessed in prion disease with positive results, further supporting the potential of immunotherapy for a variety of protein-related diseases in which clearance of the pathogenic agent is likely to alleviate symptoms
— id: 67007, year: 2006, vol: 12, page: 2569, stat: Journal Article,

Mucosal vaccination delays or prevents prion infection via an oral route
Goni, F; Knudsen, E; Schreiber, F; Scholtzova, H; Pankiewicz, J; Carp, R; Meeker, H C; Rubenstein, R; Brown, D R; Sy, M-S; Chabalgoity, J A; Sigurdsson, E M; Wisniewski, T
2005 ;133(2):413-421, Neuroscience
In recent years major outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (prion protein cellular), to a toxic and infectious form, PrP(Sc) (prion protein scrapie). None of the prionoses currently have an effective treatment. A limited number of active immunization approaches have been shown to slightly prolong the incubation period of prion infection. Active immunization in wild-type animals is hampered by auto-tolerance to PrP and potential toxicity. Here we report that mucosal vaccination with an attenuated Salmonella vaccine strain expressing the mouse PrP, is effective at overcoming tolerance to PrP and leads to a significant delay or prevention of prion disease in mice later exposed orally to the 139A scrapie strain. This mucosal vaccine induced gut anti-PrP immunoglobulin (Ig)A and systemic anti-PrP IgG. No toxicity was evident with this vaccination approach. This promising finding suggests that mucosal vaccination may be a useful method for overcoming tolerance to PrP and preventing prion infection among animal and potentially human populations at risk
— id: 75837, year: 2005, vol: 133, page: 413, stat: Journal Article,

New directions towards safer and effective vaccines for Alzheimer's disease
Goni, Fernando; Sigurdsson, Einar M
2005 Feb;7(1):17-23, Current opinion in molecular therapeutics
The first experimental vaccine against Alzheimer's disease caused encephalitis in some patients, which led to termination of the clinical trial and dealt a serious blow to this therapeutic approach. With second-generation vaccines that are likely to circumvent this side effect, this type of therapy remains promising, although more extensive animal studies are likely to be required before approval of other clinical trials. Another potential side effect, microhemorrhages within the brain vasculature, has been observed in mouse models following passive immunization, but has not been assessed in reports of active vaccination. Together, these serious adverse reactions emphasize the need to test potential Alzheimer's immunotherapy in large cohorts of primate models prior to, or at least concurrently with, human trials, as no effective therapy exists for the disease
— id: 55604, year: 2005, vol: 7, page: 17, stat: Journal Article,

Amyloid fibril formation by macrophage migration inhibitory factor
Lashuel, Hilal A; Aljabari, Bayan; Sigurdsson, Einar M; Metz, Christine N; Leng, Lin; Callaway, David J E; Bucala, Richard
2005 Dec 16;338(2):973-980, Biochemical & biophysical research communications
We demonstrate herein that human macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine expressed in the brain and not previously considered to be amyloidogenic, forms amyloid fibrils similar to those derived from the disease associated amyloidogenic proteins beta-amyloid and alpha-synuclein. Acid denaturing conditions were found to readily induce MIF to undergo amyloid fibril formation. MIF aggregates to form amyloid-like structures with a morphology that is highly dependent on pH. The mechanism of MIF amyloid formation was probed by electron microscopy, turbidity, Thioflavin T binding, circular dichroism spectroscopy, and analytical ultracentrifugation. The fibrillar structures formed by MIF bind Congo red and exhibit the characteristic green birefringence under polarized light. These results are consistent with the notion that amyloid fibril formation is not an exclusive property of a select group of amyloidogenic proteins, and contribute to a better understanding of the factors which govern protein conformational changes and amyloid fibril formation in vivo
— id: 62130, year: 2005, vol: 338, page: 973, stat: Journal Article,

Amyloid proteins: methods and protocols
Sigurdsson, Einar M
Totowa, N.J. : Humana Press, 2005,
— id: 858, year: 2005, vol: , page: , stat: ,

Histological staining of amyloid-beta in mouse brains
Sigurdsson, Einar M
2005 ;299:299-308, Methods in molecular biology
The increased availability of transgenic mouse models for studying human diseases is shifting the focus of many laboratories from in vitro to in vivo assays. The purpose of this chapter is to provide investigators with methods that will allow them to obtain well-preserved mouse brain sections to be stained with the standard histological dyes for amyloid, Congo red and thio-flavin-S. These sections can as well be used for immunohistological procedures that allow detection of amyloid-beta plaques as well as pre-amyloid deposits
— id: 56370, year: 2005, vol: 299, page: 299, stat: Journal Article,

Promising developments in prion immunotherapy
Sigurdsson, Einar M; Wisniewski, Thomas
2005 Oct;4(5):607-610, Expert review of vaccines
— id: 62131, year: 2005, vol: 4, page: 607, stat: Journal Article,

Magnetic resonance imaging of amyloid plaques in transgenic mice
Wadghiri, Youssef Zaim; Sigurdsson, Einar M; Wisniewski, Thomas; Turnbull, Daniel H
2005 ;299:365-379, Methods in molecular biology
Transgenic mice are used increasingly to model brain amyloidosis, mimicking the pathogenic processes involved in Alzheimer's disease (AD). In this chapter, a strategy is described that has been successfully used to map amyloid deposits in transgenic mouse models of AD with magnetic resonance imaging (MRI), utilizing molecular targeting vectors labeled with MRI contrast agents to enhance selectively the signal from amyloid plaques. To obtain sufficient spatial resolution for effective and sensitive mouse brain imaging, magnetic fields of 7-Tesla (T) or more are required. These are higher than the 1.5-T field strength routinely used for human brain imaging. The higher magnetic fields affect contrast agent efficiency, and determine the choice of pulse sequence parameters for in vivo MRI, all addressed in this chapter. Ex vivo imaging is also described as an important step to test and optimize protocols prior to in vivo studies. The experimental setup required for mouse brain imaging is explained in detail, including anesthesia, immobilization of the mouse head to reduce motion artifacts, and anatomical landmarks to use for the slice alignment procedure to improve image co-registration during longitudinal studies, and for subsequent matching of MRI with histology
— id: 56371, year: 2005, vol: 299, page: 365, stat: Journal Article,

Antibody mediated modulation of A beta induced neurotoxicity in cell culture
Asuni, AA; Knudsen, E; Frangione, B; Wisniewski, T; Sigurdsson, EM
2004 JUL ;25(10):S581-S582, Neurobiology of aging
— id: 47745, year: 2004, vol: 25, page: S581, stat: Journal Article,

Synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta for induction of an immune response to amyloid beta and amyloid deposits
Frangione, Blas; Wisniewski, Thomas; Sigurdsson, Einar M
2004 ;1280(5):S30-S31, Official gazette of the United States Patent & Trademark Office. Patents
The present invention relates to synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid beta peptides and amyloid deposits
— id: 97981, year: 2004, vol: 1280, page: S30, stat: Journal Article,

Monoclonal antibodies for the treatment of prion infection
Pankiewicz, J; Prelli, F; Scholtzova, H; Sadowski, M; Sigurdsson, EM; Goni, F; Kascsak, R; Kascsak, R; Carp, RI; Meeker, HC; Sy, MS; Wisniewski, T
2004 JUL ;25(10):S456-S456, Neurobiology of aging
— id: 47740, year: 2004, vol: 25, page: S456, stat: Journal Article,

Blocking the chaperoning effect of apolipoprotein E reduces beta-amyloid load in Alzheimer's disease transgenic mice
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Ripellino, James A.; Schmidt, Stephen D.; Mathews, Paul W.; Sigurdsson, Einar M.; Wisniewski, Thomas
2004 ;62(7, Suppl. 5):A522-A447, Neurology
— id: 97610, year: 2004, vol: 62, page: A522, stat: Journal Article,

A Synthetic Peptide Blocking the Apolipoprotein E/{beta}-Amyloid Binding Mitigates {beta}-Amyloid Toxicity and Fibril Formation in Vitro and Reduces {beta}-Amyloid Plaques in Transgenic Mice
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Ripellino, James A; Li, Yongsheng; Schmidt, Stephen D; Mathews, Paul M; Fryer, John D; Holtzman, David M; Sigurdsson, Einar M; Wisniewski, Thomas
2004 Sep;165(3):937-948, American journal of pathology
Alzheimer's disease (AD) is associated with accumulation of beta-amyloid (Abeta). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Abeta, promoting its conformational transformation from soluble Abeta into toxic aggregates. We determined if blocking the apoE/Abeta interaction reduces Abeta load in transgenic (Tg) AD mice. The binding site of apoE on Abeta corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Abeta12-28P). This changed the peptide's properties, making it non-fibrillogenic and non-toxic. Abeta12-28P competitively blocks binding of full-length Abeta to apoE (IC(50) = 36.7 nmol). Furthermore, Abeta12-28P reduces Abeta fibrillogenesis in the presence of apoE, and Abeta/apoE toxicity in cell culture. Abeta12-28P is blood-brain barrier-permeable and in AD Tg mice inhibits Abeta deposition. Tg mice treated with Abeta12-28P for 1 month had a 63.3% reduction in Abeta load in the cortex (P = 0.0043) and a 59.5% (P = 0.0087) reduction in the hippocampus comparing to age-matched control Tg mice. Antibodies against Abeta were not detected in sera of treated mice; therefore the observed therapeutic effect of Abeta12-28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Abeta and its pathological chaperones may be beneficial for treatment of beta-amyloid deposition in AD
— id: 44511, year: 2004, vol: 165, page: 937, stat: Journal Article,

In vivo magnetic resonance of amyloid plaques in Alzheimer's disease model mice
Sigurdsson, E; Wadghiri, YZ; Sadowski, M; Elliott, JI; Li, YS; Scholtzova, H; Tang, CY; Aguinaldo, G; Duff, K; Turnbull, DH; Wisniewski, T
The living brain and Alzheimer's disease Berlin : Springer, 2004,
A key feature of Alzheimer's disease (AD) is the deposition of the amyloid beta (Abeta) as neuritic plaques in the brain. Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP-PS1), develop Abeta plaques similar to AD patients and are currently the most widely used models of AD. The definitive diagnosis of AD still requires post-mortem examination. We have developed a novel method for the detection of Abeta plaques in the brains of AD model transgenic mice using magnetic resonance micro-imaging (muMRI). Our method is dependent on ligands that bind to AD amyloid lesions, allowing their detection by muMRI. These ligands are Abeta1-40 peptides, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). When these are systemically injected with mannitol to transiently open the blood-brain barrier, we are able to detect the majority of amyloid lesions. The number of lesions detected by muMRI showed a statistically significant correlation with the Abeta burden determined by histology. This approach, with additional development, may be used to detect amyloid lesions in humans. Similar methods may also be used to image other conformational neurodegenerative disorders
— id: 4970, year: 2004, vol: , page: 47, stat: Chapter,

An attenuated immune response is sufficient to enhance cognition in an Alzheimer's disease mouse model immunized with amyloid-beta derivatives
Sigurdsson, Einar M; Knudsen, Elin; Asuni, Ayodeji; Fitzer-Attas, Cheryl; Sage, Daniel; Quartermain, David; Goni, Fernando; Frangione, Blas; Wisniewski, Thomas
2004 Jul 14;24(28):6277-6282, Journal of neuroscience
Immunization with amyloid-beta (Abeta) 1-42 has been shown to reduce amyloid burden and improve cognition in Alzheimer's disease (AD) model mice. In a human trial, possible cognitive benefit was found but in association with significant toxicity in a minority of patients. We proposed that immunization with nonfibrillogenic Abeta derivatives is much less likely to produce toxicity and have previously shown that one such derivative (K6Abeta1-30) can reduce amyloid burden in mice to a similar extent as Abeta1-42. Here, we immunized AD model mice (Tg2576) with Abeta1-30[E18E19] or with K6Abeta1-30[E18E19]. These peptides were designed to be nontoxic and to produce less T-cell response, which has been linked to toxicity. K6Abeta1-30[E18E19] induced primarily an IgM response, whereas Abeta1-30[E18E19] induced an IgG titer that was lower than previously seen with K6Abeta1-30 or Abeta1-42. However, both treated animal groups performed better than Tg controls in the radial arm maze. Amyloid burden was similar in Abeta1-30[E18E19]-vaccinated mice and their Tg controls, whereas the number of medium and small sized plaques was reduced (29-34%) in K6Abeta1-30[E18E19]-immunized mice compared with Tg controls. Amyloid burden in these mice correlated inversely with plasma IgM levels. The cognitive benefit and amyloid reduction in the K6Abeta1-30[E18E19]-vaccinated mice are likely to be related to peripheral clearance of Abeta, because IgM does not cross the blood-brain barrier because of its large size. Our results indicate that these nontoxic Abeta derivatives produce an attenuated antibody response, which is less likely to be associated with negative side effects while having cognitive benefits
— id: 44513, year: 2004, vol: 24, page: 6277, stat: Journal Article,

Modest immune response elicited by A beta derivatives in TG2576 mice improves cognition
Sigurdsson, EM; Knudsen, E; Asuni, A; Sage, D; Goni, F; Quartermam, D; Frangione, B; Wisniewski, T
2004 JUL ;25(10):S576-S576, Neurobiology of aging
— id: 47744, year: 2004, vol: 25, page: S576, stat: Journal Article,

In vivo magnetic resonance imaging of amyloid plaques in mice with a non-toxic A beta derivative
Sigurdsson, EM; Wadghiri, YZ; Blind, JA; Knudsen, E; Asuni, A; Sadowski, M; Turnbull, DH; Wisniewski, T
2004 JUL ;25(10):S57-S57, Neurobiology of aging
— id: 47715, year: 2004, vol: 25, page: S57, stat: Journal Article,

Detection of Alzheimer's amyloid lesions in transgenic mice by magnetic resonance imaging
Sigurdsson, EM; Wadghiri, YZ; Li, YS; Elliott, JI; Tang, CY; Aguilnaldo, G; Duff, K; Pappolla, M; Watanabe, M; Scholtzova, H; Turnbull, DH; Wisniewski, T
2004 FEB ;25(2):251-251, Neurobiology of aging
— id: 42486, year: 2004, vol: 25, page: 251, stat: Journal Article,

Imaging and therapeutic approaches for beta-sheet structures in prion and Alzheimer's diseases
Wisniewski, T; Pankiewicz, J; Scholtzova, H; Fernando, G; Chabalgoity, JA; Ji, Y; Wadghiri, YZ; Gan, WB; Tang, CY; Turnbull, DH; Mathis, CA; Kascsak, R; Klunk, WE; Carp, RI; Frangione, B; Sigurdsson, EM; Sadowski, M
2004 ;25(2):S30-S31, Neurobiology of aging
— id: 97595, year: 2004, vol: 25, page: S30, stat: Journal Article,

Reduction of beta-amyloid load in Alzheimer's disease transgenic mice by competitive blocking of beta-amyloid binding to apolipoprotein E
Wisniewski, T; Pankiewicz, J; Scholtzova, H; Schmidt, SD; Mathews, PM; Sigurdsson, EM; Sadowski, M
2004 JUL ;25(10):S583-S583, Neurobiology of aging
— id: 47746, year: 2004, vol: 25, page: S583, stat: Journal Article,

In vivo imaging of amyloid plaques in AD and prion disease model mice
Wisniewski, T; Sigurdsson, EM; Wadghiri, YZ; Carp, R; Tang, CY; Turnbull, DH; Mathis, C; Klunk, WE; Gan, WB; Sadowski, M
2004 APR ;25(12):S29-S29, Neurobiology of aging
— id: 42446, year: 2004, vol: 25, page: S29, stat: Journal Article,

Immunization with amyloid - beta derivatives improves cognition while provoking a weak antibody response
Knudsen, E. L.; Wisniewski, T.; Quartermain, D.; Sage, D.; Scholtzova, H.; Frangione, B.; Sigurdsson, E. M.
2003 ;2003(5):Abstract No. 133.10-S31, Society for Neuroscience Abstract Viewer & Itinerary Planner
We have reported that an amyloid-beta derivative, K6Abeta1-30-NH2 reduces amyloid burden in mice to a similar extent as previously shown for Abeta1-42 (Am J Pathol 159:439-47,2001). This derivative may be a safer alternative to Alzheimer's vaccination with Abeta1-42 because it has a low beta-sheet content while maintaining the main antigenic sites of Abeta. To determine the in vivo effect of other derivatives with similar in vitro properties, we immunized Tg2576 mice with Abeta1-30-NH2, in which amino acids 18 and 19 were substituted with glutamate (Abeta1-30E18E19). In a parallel study, mice were immunized with K6Abeta1-30E18E19. Freund's adjuvant was used to allow a comparison with our findings with K6Abeta1-30-NH2. Antibody titers were detectable, but much lower than we had observed for K6Abeta1-30-NH2 or Abeta1-42, indicating that the central hydrophobic region of Abeta may have an epitope important for modulating humoral response. Cognitive performance was assessed in a radial arm maze before sacrifice at 19-21 months. Control Tg mice had more errors than their wild-type littermates (p<0.01), and the Abeta1-30E18E19-treated mice (p<0.05). Mice receiving K6Abeta1-30E18E19 also performed better than their Tg controls (p<0.05). Histologically, no difference was observed in brain amyloid plaque burden in 6E10 stained brain sections from the Abeta1-30E18E19-vaccinated mice, compared to vehicle treated mice. Furthermore, amyloid burden did not correlate with cognitive performance. Analysis of plaque burden in the K6Abeta1-30E18E19-immunized mice is underway, as well as measurements of brain levels of Abeta to determine if these values will provide a better correlation with cognitive performance. A robust antibody response and a diminished plaque burden may not be necessary for a therapeutic effect of Abeta derived vaccines
— id: 97630, year: 2003, vol: 2003, page: Abstract No. 133.10, stat: Journal Article,

Inhibition of apolipoprotein E binding to amyloid - beta decreases fibril formation and deposition in vitro and in vivo
Sadowski, M.; Ji, Y.; Scholtzova, H.; Pankiewicz, J.; Sigurdsson, E. M.; Wisniewski, T.
2003 ;2003(5 Supplement 1):Abstract No. 666.6-118, Society for Neuroscience Abstract Viewer & Itinerary Planner
Deposition of amyloid-beta (Abeta) in form of the senile plaques and in vessel walls is a hallmark of Alzheimer's disease (AD). Apolipoprotein E (apoE) is known to act as a pathological chaperone by increasing the beta-sheet content of Abeta, promoting its fibrillization, toxicity, and deposition in the brain. ApoE binds to residues 12-28 of Abeta. We report in vitro and in vivo data on the blocking of the apoE/Abeta interaction by a synthetic peptide homologues to residues 12-28 of Abeta. To eliminate any residual toxicity and fibrillogenic potential the peptide sequence was altered by replacing a valine in position 18 by a proline (Abeta12-28P). On ELISA Abeta12-28P demonstrates high affinity binding to apoE and in competitive binding experiments inhibits the binding of apoE to Abeta42. Abeta12-28P also reduces the toxicity of Abeta in cell culture, as well as blocking the enhanced fibril formation of Abeta in the presence of apoE4, measured by the Thioflavin-T assay. The in vivo effect of Abeta12-28P was assessed in double transgenic (Tg) APP/PS1 AD mice which received 1mg of Abeta12-28P or placebo three times a week for four weeks. There was an approximately five fold reduction of the total and fibrillar Abeta in treated mice comparing to control (p<0.05). Also, Abeta40 and Abeta42 levels in the brain demonstrated a 40-60% reduction of both species in the total Abeta fraction and in the soluble Abeta fraction in treated mice comparing to controls. No significant titer of anti-Abeta antibodies in treated animals was detected, indicating that the effect of Abeta12-28P on Abeta deposition observed in vivo is not immune mediated. Overall, compounds blocking the interaction between Abeta and its pathological chaperones such as apoE (or alpha1anti-chymotrypsin, perlecan etc.) can be considered as an alternative approach for the treatment of beta-amyloidosis in AD
— id: 97615, year: 2003, vol: 2003, page: Abstract No. 666.6, stat: Journal Article,

Blocking apolipoprotein E/beta-amyloid interaction as a therapeutic approach for Alzheimer's disease
Sadowski, Marcin; Ji, Yong; Scholtzova, Henrieta; Sigurdsson, Einar M.; Wisniewski, Thomas
2003 ;60(5 Supplement 1):A68-118, Neurology
— id: 97613, year: 2003, vol: 60, page: A68, stat: Journal Article,

Copper modulates prion infectivity
Sigurdsson, E. M.; Brown, D.; Alim, M. A.; Scholtzova, H.; Carp, R.; Meeker, H. C.; Prelli, F.; Frangione, B.; Wisniewski, T.
2003 ;2003(47):Abstract No. 631.2-46202, Society for Neuroscience Abstract Viewer & Itinerary Planner
The prion protein (PrP) is a copper binding protein; however, the role of copper in prion infection is unclear. Under some conditions copper facilitates refolding of denatured PrPSc into a protease resistant and infectious form. Hence copper may enhance the infectivity of the prion protein. To determine the feasibility of copper targeted therapy for prion disease, we treated mice (n=10 per group) with d-penicillamine (d-PEN; 100 mg/kg, i.p.), immediately following scrapie inoculation (139A strain, i.p.). Subsequent drug injections were daily, five days per week. d-PEN delayed the onset of prion disease in the mice (p=0.002). The effect was more pronounced at the 1000-fold dilution of agent (d-PEN=179 +- 3 days, VEH=165 +- 4, p=0.006), but a trend for a delay was observed at the 10-fold dilution (d-PEN=153 +- 2, VEH=146 +- 3, p=0.1). As expected, d-PEN reduced brain copper levels (p<0.01) by 26% (10-fold dil.; p=0.04) and 32% (1000-fold dil.; p=0.02), compared to control animals. Brain levels of iron and zinc were not reduced. To further support the notion that the therapeutic effect of d-PEN was mediated through its copper chelating properties, brain homogenates from terminally ill 139A infected mice were incubated with copper and d-PEN. Following a 72 h incubation, copper sulfate increased aggregation of the prion protein in a dose dependent manner, resulting in an enhanced resistance to proteinase K. This effect was counteracted by co-incubation with d-PEN. These findings support the proposed in vivo effect of d-PEN in delaying the onset of prion disease in these mice. Copper chelator-based therapy may benefit those incubating prion disease but this approach may be more effective at higher doses and/or in a multi-targeted combinational therapy
— id: 97631, year: 2003, vol: 2003, page: Abstract No. 631.2, stat: Journal Article,

Copper chelation delays the onset of prion disease
Sigurdsson, Einar M; Brown, David R; Alim, Muhammad A; Scholtzova, Henrieta; Carp, Richard; Meeker, Harry C; Prelli, Frances; Frangione, Blas; Wisniewski, Thomas
2003 Nov 21;278(47):46199-46202, Journal of biological chemistry
The prion protein (PrP) binds copper and under some conditions copper can facilitate its folding into a more protease resistant form. Hence, copper levels may influence the infectivity of the scrapie form of prion protein (PrPSc). To determine the feasibility of copper-targeted therapy for prion disease, we treated mice with a copper chelator, D-(-)-penicillamine (D-PEN), starting immediately following intraperitoneal scrapie inoculation. D-PEN delayed the onset of prion disease in the mice by about 11 days (p = 0.002), and reduced copper levels in brain by 29% (p < 0.01) and in blood by 22% (p = 0.03) compared with control animals. Levels of other metals were not significantly altered in the blood or brain. Modest correlation was observed between incubation period and levels of copper in brain (p = 0.08) or blood (p = 0.04), indicating that copper levels are only one of many factors that influence the rate of progression of prion disease. In vitro, copper dose-dependently enhanced the proteinase K resistance of the prion protein, and this effect was counteracted in a dose-dependent manner by co-incubation with D-PEN. Overall, these findings indicate that copper levels can influence the conformational state of PrP, thereby enhancing its infectivity, and this effect can be attenuated by chelator-based therapy
— id: 48185, year: 2003, vol: 278, page: 46199, stat: Journal Article,

Anti-prion antibodies for prophylaxis following prion exposure in mice
Sigurdsson, Einar M; Sy, Man-Sun; Li, Ruliang; Scholtzova, Henrieta; Kascsak, Richard J; Kascsak, Regina; Carp, Richard; Meeker, Harry C; Frangione, Blas; Wisniewski, Thomas
2003 Jan 23;336(3):185-187, Neuroscience letters
Prion disease is characterized by a conformational change of the normal form of the prion protein (PrP(C)) to the scrapie-associated form (PrP(Sc)). Since the emergence of new variant Creutzfeldt-Jakob disease a potentially large human population is at risk for developing prion disease. Currently, no effective treatment or form of post-exposure prophylaxis is available for prion disease. We recently showed that active immunization with recombinant PrP prolongs the incubation period of scrapie. Here we show that anti-PrP antibodies following prion exposure are effective at increasing the incubation period of the infection. Stimulation of the immune system is an important therapeutic target for the prion diseases, as well as for other neurodegenerative illnesses characterized by abnormal protein conformation
— id: 34146, year: 2003, vol: 336, page: 185, stat: Journal Article,

Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging
Wadghiri, Youssef Zaim; Sigurdsson, Einar M; Sadowski, Marcin; Elliott, James I; Li, Yongsheng; Scholtzova, Henrieta; Tang, Cheuk Ying; Aguinaldo, Gilbert; Pappolla, Miguel; Duff, Karen; Wisniewski, Thomas; Turnbull, Daniel H
2003 Aug;50(2):293-302, Magnetic resonance in medicine
The presence of amyloid-beta (Abeta) plaques in the brain is a hallmark pathological feature of Alzheimer's disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP/PS1), develop Abeta plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Abeta. However, at present there is no in vivo whole-brain imaging method to detect Abeta plaques in mice or men. A novel method is presented to detect Abeta plaques in the brains of transgenic mice by magnetic resonance microimaging (muMRI). This method uses Abeta1-40 peptide, known for its high binding affinity to Abeta, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Abeta1-40, with mannitol to transiently open the blood-brain barrier (BBB), enabled the detection of many Abeta plaques. Furthermore, the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Abeta in AD transgenic mice, and suggests that diagnostic MRI methods to detect Abeta in AD patients may ultimately be feasible
— id: 38795, year: 2003, vol: 50, page: 293, stat: Journal Article,

in vivo magnetic resonance imaging of amyloid plaques in AD model mice
Wisniewski, T.; Sigurdsson, E. M.; Wadghiri, Y. Z.; Sadowski, M.; Scholtzova, H.; Tang, C. Y.; Aguilnaldo, G.; Duff, K.; Turnbull, D. H.
2003 ;2003(2):Abstract No. 203.7-302, Society for Neuroscience Abstract Viewer & Itinerary Planner
Amyloid deposition in Alzheimer's disease (AD) occurs many years before cognitive impairment. Brain imaging techniques targeting plaques will have an important diagnostic value and may help in identifying individuals in preclinical stages of AD. Magnetic resonance imaging (MRI) has a much higher resolution than positron enhanced tomography (PET) imaging and, therefore, is a more sensitive method to detect amyloid plaques. In our initial proof-of-concept studies (Magnetic Resonance in Medicine, in press), we utilized Abeta1-40 peptide, labeled with gadolinium or monocrystalline iron oxide nanoparticles (MION). When either of these ligands is injected in vivo systemically with mannitol to transiently open the blood-brain-barrier, we are able to image ex vivo the majority of Abeta plaques in Tg mice. Using Gd labeled Abeta1-40 and in vivo muMRI, we can also detect a substantial percentage of amyloid lesions. There is a high correlation between the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry. Clinical use of Abeta1-40 is not feasible because it may add to the plaque burden. As a safer approach, we are using gadolinium labeled K6Abeta1-30, a non-toxic Abeta derivative with low propensity to form beta-sheet, while maintaining high affinity for Abeta. Our initial findings indicate that this compound has a similar effect as gadolinium labeled Abeta1-40 in allowing in vivo detection of amyloid plaques in Tg mice. We are currently exploring various ways to enhance the uptake of this compound into the brain. This approach may lead to a diagnostic MRI method to detect Abetaplaques in AD patients
— id: 97618, year: 2003, vol: 2003, page: Abstract No. 203.7, stat: Journal Article,

Immunization approaches for the treatment of prion disease
Wisniewski, Thomas; Sy, Man-Sun; Sadowski, Marcin; Kascsak, Richard J.; Kascsak, Regina; Carp, Richard; Goni, Fernando; Sigurdsson, Einar
2003 ;60(5 Supplement 1):A250-302, Neurology
— id: 97619, year: 2003, vol: 60, page: A250, stat: Journal Article,

A safer vaccine for Alzheimer's disease?
Frangione, B; Wisniewski, T; Sigurdsson, EM
2002 Jul-Aug;23(1):1579-, Neurobiology of aging
— id: 32430, year: 2002, vol: 23, page: 1579, stat: Journal Article,

Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging
Poduslo, JF; Wengenack, T; Curran, GV; Macura, S; Borowski, B; Jack, C; Wisniewski, T; Sigurdsson, E
2002 ;23(1):1550-329, Neurobiology of aging
— id: 97596, year: 2002, vol: 23, page: 1550, stat: Journal Article,

Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging
Poduslo, JF; Wengenack, TM; Curran, GL; Wisniewski, T; Sigurdsson, EM; Macura, SI; Borowski, BJ; Jack, CR
2002 Jun;81(7):61-61, Journal of neurochemistry
— id: 32368, year: 2002, vol: 81, page: 61, stat: Journal Article,

Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging
Poduslo, Joseph F; Wengenack, Thomas M; Curran, Geoffry L; Wisniewski, Thomas; Sigurdsson, Einar M; Macura, Slobodon I; Borowski, Bret J; Jack, Clifford R Jr
2002 Nov;11(2):315-329, Neurobiology of disease
Smart molecular probes for both diagnostic and therapeutic purposes are expected to provide significant advances in clinical medicine and biomedical research. We describe such a probe that targets beta-amyloid plaques of Alzheimer's disease and is detectable by magnetic resonance imaging (MRI) because of contrast imparted by gadolinium labeling. Three properties essential for contrast enhancement of beta-amyloid plaques on MRI exist in this smart molecular probe, putrescine-gadolinium-amyloid-beta peptide: (1) transport across the blood-brain barrier following intravenous injection conferred by the polyamine moiety, (2) binding to plaques with molecular specificity by putrescine-amyloid-beta, and (3) magnetic resonance imaging contrast by gadolinium. MRI was performed on ex vivo tissue specimens at 7 T at a spatial resolution approximating plaque size (62.5 microm(3)), in order to prove the concept that the probe, when administered intravenously, can selectively enhance plaques. The plaque-to-background tissue contrast-to-noise ratio, which was precisely correlated with histologically stained plaques, was enhanced more than nine-fold in regions of cortex and hippocampus following intravenous administration of this probe in AD transgenic mice. Continuing engineering efforts to improve spatial resolution are underway in MRI, which may enable in vivo imaging at the resolution of individual plaques with this or similar contrast probes. This could enable early diagnosis and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed
— id: 62132, year: 2002, vol: 11, page: 315, stat: Journal Article,

SAFETY OF POTENTIAL VACCINES FOR ALZHEIMER'S DISEASE
Scholtzova, H.; Wisniewski, T.; Ahlawat, S.; Watanabe, M.; Quartermain, D.; Frangione, B.; Sigurdsson, E. M.
2002 ;2002(6):Abstract No. 227.1-46202, Society for Neuroscience Abstract Viewer & Itinerary Planner
Abeta1-42 vaccination trials were recently terminated because of cerebral inflammation, which may be due to Abeta toxicity and/or autoimmunity. Abeta forms inflammatory/toxic fibrils, may seed fibril formation and crosses the blood brain barrier (BBB) in experimental animals. Because of attenuated immune response, the elderly may not clear injected Abeta1-42, which may then initiate and/or enhance amyloid angiopathy and plaque formation. Therefore, it is safer to use immunogenic Abeta derivatives, which are less likely to be toxic. Unlike Abeta1-42, K6Abeta1-30 is non-fibrillogenic and non-toxic in human cell culture but diminishes amyloid burden to a similar extent as reported for Abeta1-42. Additionally, ramified IL-1beta positive microglia, associated with the plaques, are absent in the immunized mice indicating reduced inflammation in these animals. We are currently comparing the therapeutic potential of these two compounds in alum adjuvants, which are approved for human use. Our behavioral findings in a year old Tg2576 mice show no difference between these groups and controls in various sensorimotor tasks, linear maze and water maze. However, in the radial arm maze, vaccinated Tg mice and their non-Tg littermates performed equally well and had fewer errors than Tg controls (p=0.008). These groups are being evaluated at a higher amyloid burden and subsequently their brain pathology will be assessed. Overall, the use of nontoxic Abeta derivatives and/or Abeta clearing compounds with very limited access into the CNS, such as IgM, may prove to have reduced side effects compared to Abeta and/or IgG-based immunization
— id: 97632, year: 2002, vol: 2002, page: Abstract No. 227.1, stat: Journal Article,

VACCINATION DELAYS THE ONSET OF PRION DISEASE IN MICE
Sigurdsson, E. M.; Brown, D. R.; Daniels, M.; Kascsak, R. J.; Kascsak, R.; Carp, R.; Meeker, H. C.; Watanabe, M.; Scholtzova, H.; Frangione, B.; Wisniewski, T.
2002 ;2002(6):Abstract No. 692.15-413, Society for Neuroscience Abstract Viewer & Itinerary Planner
The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has shown therapeutic potential in mouse models of another neurodegenerative condition, namely Alzheimers disease. Here we report that immunization with recombinant mouse prion protein delays the onset of prion disease in mice (Am. J. Pathol., in press). Vaccination was performed both prior to and after peripheral exposure to the mouse-adapted scrapie strain 139A. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized prior to exposure (p = 0.040-0.002). The increase in the incubation period closely correlated with the anti-prion antibody titer (p = 0.017-0.0001). Histological and Western blot evaluations of the brains of the treated-and control groups did not reveal any apparent differences in the degree of spongiform change or levels of scrapie prion. This was expected because the mice were killed when they scored positive for three consecutive weeks for behavioral signs of prion infection. Overall, the vaccination-mediated delay in prion disease onset is highly reproducible, correlates well with antibody titer and indicates that a similar approach may work in humans or other mammalian species at risk for prion disease
— id: 97633, year: 2002, vol: 2002, page: Abstract No. 692.15, stat: Journal Article,

Immunization delays the onset of prion disease in mice
Sigurdsson, Einar M; Brown, David R; Daniels, Maki; Kascsak, Richard J; Kascsak, Regina; Carp, Richard; Meeker, Harry C; Frangione, Blas; Wisniewski, Thomas
2002 Jul;161(1):13-17, American journal of pathology
The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has been shown to be effective in mouse models of another neurodegenerative condition, namely Alzheimer's disease. Here we report that vaccination with recombinant mouse prion protein delays the onset of prion disease in mice. Vaccination was performed both before peripheral prion exposure and after exposure. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized before exposure. The increase in the incubation period closely correlated with the anti-prion protein antibody titer. This promising finding suggests that a similar approach may work in humans or other mammalian species at risk for prion disease
— id: 32479, year: 2002, vol: 161, page: 13, stat: Journal Article,

A safer vaccine for Alzheimer's disease?
Sigurdsson, Einar M; Wisniewski, Thomas; Frangione, Blas
2002 Nov-Dec;23(6):1001-1008, Neurobiology of aging
Recent reports indicate that amyloid-beta (Abeta) vaccine-based therapy for Alzheimer's disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Abeta1-42 may not be appropriate in humans because it crosses the blood-brain barrier, can seed fibril formation, and is highly fibrillogenic. Abeta1-42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Abeta derivative may be a safer therapeutic approach to impede the progression of Abeta-related histopathology in AD. Although the site of action of the anti-Abeta antibodies has been suggested to be within the brain, peripheral clearance of Abeta may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Abeta compared to brain Abeta. This disruption of the equilibrium between central and peripheral Abeta should then result in efflux of Abeta out of the brain, and subsequent removal of plaques. Abeta therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Abeta derived vaccines should include T(h) epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD
— id: 32918, year: 2002, vol: 23, page: 1001, stat: Journal Article,

Infectivity of amyloid diseases
Sigurdsson, Einar M; Wisniewski, Thomas; Frangione, Blas
2002 Sep;8(9):411-413, Trends in molecular medicine
To date, transmissibility of amyloid diseases has not been thoroughly investigated. Although only some of these conformational disorders are considered infectious, all amyloid diseases could be infectious under certain conditions. For transmissibility, endogenous expression of an amyloidogenic peptide required, as well as the presence of an inoculum that is rich in amyloid fibrils and/or their precursors. Notably, administration of one type of amyloid might result in deposition of a different amyloid. Various cofactors could be essential for transmission - some might chaperone the amyloid peptides and/or fibrils, thereby directly facilitating their propagation; others might indirectly stabilize and/or increase levels of conformers with a high beta-sheet content. It is possible that these chaperones are induced by inflammation, which itself can lead to secondary amyloidosis. Thus, amyloid-related therapeutic approaches should not be based on administration of amyloidogenic peptides in conjunction with an inflammatory stimulus, such as in a recently halted clinical trial for Alzheimer's disease
— id: 32920, year: 2002, vol: 8, page: 411, stat: Journal Article,

Immunization for Alzheimer's disease
Sigurdsson, EM; Frangione, B; Wisniewski, T
2002 Jun;56(2):135-142, Drug development research
The recent termination of a Phase II clinical trial in which volunteers with Alzheimer's disease (AD) were vaccinated with Amyloid-beta (AP)1-42, has cast doubt on the feasibility of this therapeutic approach. While the exact reasons for the cerebral inflammation in these patients is being determined, it is difficult to evaluate the cause of these adverse effects. The most likely reasons are Abeta1-42 toxicity and/or autoimmunity. Abeta vaccination approaches are based on the hypothesis that Abeta deposition and toxicity are central to the pathogenesis of AD. Therefore, it is counterintuitive to use the whole Abeta peptide for human vaccination. Abeta1-40/42 is a major plaque component that forms inflammatory/toxic fibrils as observed in many in vitro and in vivo studies. Furthermore, numerous studies have shown that Abeta1-40/42 bidirectionally crosses the blood-brain barrier (BBB) in experimental animals. Additionally, in vitro and in vivo studies indicate that minute amounts of Abeta1-42 may seed fibril/amyloid formation. The elderly, a target population for AD therapy, often have a poor immune response to vaccines, which enhances the gravity of these safety concerns. In these patients with an attenuated immune reaction, injected Abeta1-42 may initiate and/or enhance congophilic angiopathy, which eventually may result in reduced cerebral blood flow and/or intracerebral bleeding. Abeta1-42 may also cross the BBB and once within the brain parenchyma it may contribute to plaque formation and/or co-deposit on plaques. Together, these effects within blood vessels and/or brain parenchyma may actually enhance the progression of AD. Given the potential serious side effects of Abeta1-42 vaccination, it is safer to use immunogenic Abeta derivatives, which are less likely to be toxic. The main immunogenic epitopes of Abeta1-42 are contained within the first 30 amino acids of the peptide. Taking this into account, we have developed soluble antigenic Abeta derivatives, which are nonfibrillogenic and nontoxic in human cell culture. Our prototype peptide, K6Abeta1-30-NHz, diminishes amyloid burden to a similar extent as reported for Abeta1-42. Additionally, ramified IL-1beta-positive microglia as well as phagocytes, associated with the Abeta plaques, were absent in the immunized mice, indicating reduced inflammation in these animals at the time point examined. Autoimmunity may be the culprit if follow-up studies reveal that the brain inflammation is related to antibody interactions with AD and/or amyloid precursor protein (APP). In such a scenario, any vaccination approach targeting A(3 can have similar consequences, although preventive treatment initiated prior to amyloid deposition may not result in these adverse reactions. T-cell-related autoimmunity may also be involved and can be expected to be less with Abeta derivatives not containing certain T-cell epitopes. An alternative to the active vaccination approach is passive immunization, which is associated with a lower risk of irreversible autoimmunity. This approach may also be used in patients with a muted immune response to the vaccine. However, in a chronic disease such as AD repeated antibody injections may lead to an anti-idiotype response and the resulting serum immune complexes can cause vasculitis and/or glomerulonephritis. Reduction of soluble Abeta within the peripheral system may be a critical part of the pathway that reduces cerebral plaque burden in Tg mice and ultimately in AD patients. Overall, the use of nontoxic A(3 derivatives and/or antibodies with very limited access into the CNS, such as IgM, may prove to have reduced si Any therapeutic approach will be more effective when used prophylactically because of neuronal loss and increased amyloid burden in the later stages of AD. Reversal of clinical symptoms cannot be expected and early diagnosis of AD may be needed for effective therapy. (C) 2002 Wiley-Liss, Inc
— id: 32447, year: 2002, vol: 56, page: 135, stat: Journal Article,

In vivo detection of Alzheimer's amyloid by magnetic resonance imaging
Sigurdsson, EM; Wadghiri, YZ; Li, Q; Scholtzova, H; Tang, CY; Aguilnaldo, JG; Duff, K; Pappolla, M; Elliott, JI; Watanabe, M; Turnbull, DH; Wisniewski, T
2002 Jul-Aug;23(1):1307-, Neurobiology of aging
— id: 32425, year: 2002, vol: 23, page: 1307, stat: Journal Article,

Prion related diseases
Wisniewski T; Sigurdsson E
2002;:- [Web site], 2002-, Emedicine
— id: 150918, year: 2002, vol: , page: , stat: Web Site,

PASSIVE IMMUNIZATION WITH ANTI - PrP ANTIBODIES PROLONGS PRION INCUBATION PERIOD
Wisniewski, T.; Sy, M. S.; Li, R.; Scholtzova, H.; Kascsak, R. J.; Kascsak, R.; Carp, R.; Meeker, H. C.; Frangione, B.; Sigurdsson, E. M.
2002 ;2002(6):Abstract No. 692.16-413, Society for Neuroscience Abstract Viewer & Itinerary Planner
The prion diseases are a rapidly fatal group of neurodegenerative disorders, which currently have no effective therapy. Recently we have shown that active immunization with recombinant PrP protein increases the incubation period in mice exposed peripherally to the 139A strain of scrapie agent (Am.J.Pathol., in press). The antibody titers correlated with the increased incubation. We have extended these observations by using 6 different monoclonal anti-mouse PrP antibodies for passive immunization, with epitopes that span the murine PrP protein. Intraperitoneal antibody injections were performed weekly, starting immediately after and 1 month following peripheral exposure to scrapie strain 139A at two different dilutions. We found a statistically significant prolongation of the incubation period from scrapie exposure to the onset of clinical symptoms. These initial findings suggest that passive immunization can be used to prolong the incubation period among individuals with a known exposure to the prion agent
— id: 97634, year: 2002, vol: 2002, page: Abstract No. 692.16, stat: Journal Article,

Therapeutics in Alzheimer's and prion diseases
Wisniewski, T; Brown, D R; Sigurdsson, E M
2002 Aug;30(4):574-578, Transactions (Biochemical Society (Great Britain))
There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-beta peptide (sA beta) to A beta plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to the disease-associated form, PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed 'beta-sheet breakers' that directly target the abnormal conformational change both for A beta- and PrP(Sc)-related deposits. In addition, immune system activation can serve as beta-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders
— id: 32922, year: 2002, vol: 30, page: 574, stat: Journal Article,

Vaccination delays the onset of prion disease in mice
Wisniewski, T; Scholtzova, H; Watanabe, M; Ji, Y; Frangione, B; Sigurdsson, EM; Brown, DR; Daniels, M; Kasesak, RJ; Kascsak, R
2002 Jul-Aug;23(1):496-, Neurobiology of aging
— id: 32412, year: 2002, vol: 23, page: 496, stat: Journal Article,

Immunization treatment approaches in Alzheimer's and prion diseases
Wisniewski, Thomas; Sigurdsson, Einar M
2002 Sep;2(5):400-404, Current neurology & neuroscience reports
There is growing realization that many neurodegenerative conditions have the same underlying pathogenetic mechanism: a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease (AD), amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid beta (sAbeta) to Abeta plaques, whereas in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. Different approaches under development include drugs that affect the processing of the precursor proteins, enhance clearance of the amyloidogenic protein, and inhibit or prevent the conformation change. Particularly interesting are recent studies of immune system activation, which appear to increase the clearance of the disease-associated protein. These immunologically based approaches are highly effective in animal models of these disorders, and in these model systems are associated with no obvious side effects. In transgenic mice with AD-related pathology, immunization has also been shown to prevent age-related cognitive impairment. However, the first clinical trial of this approach in AD patients was associated with unacceptable toxicity. These immune-based treatment approaches have great potential as rational therapies for this devastating group of disorders, but additional development is needed before they can be safely applied to humans
— id: 32923, year: 2002, vol: 2, page: 400, stat: Journal Article,

Distinct properties of wild-type and the amyloidogenic human cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type
Calero M; Pawlik M; Soto C; Castano EM; Sigurdsson EM; Kumar A; Gallo G; Frangione B; Levy E
2001 Apr;77(2):628-637, Journal of neurochemistry
Variant human cystatin C (L68Q) is an amyloidogenic protein. It deposits in the cerebral vasculature of Icelandic patients with cerebral amyloid angiopathy, leading to stroke. Wild-type and variant cystatin C are cysteine proteinase inhibitors which form concentration dependent inactive dimers; however, variant cystatin C dimerizes at lower concentrations and has an increased susceptibility to a serine protease. We studied the effect of the L68Q amino acid substitution on cystatin C properties, utilizing full length cystatin C purified in mild conditions from media of cells stably transfected with either the wild-type or variant cystatin C genes. The variant cystatin C forms fibrils in vitro detectable by electron microscopy in conditions in which the wild-type protein forms amorphous aggregates. We also show by circular dichroism, steady-state fluorescence and Fourier-transformed infrared spectroscopy that the amino acid substitution modifies cystatin C structure by destabilizing alpha-helical structures and exposing the tryptophan residue to a more polar environment, yielding a more unfolded molecule. These spectral changes demonstrate that variant cystatin C has a three-dimensional structure different from that of the wild-type protein. The structural differences between variant and wild-type cystatin C account for the susceptibility of the variant protein to unfolding, proteolysis and fibrillogenesis
— id: 20351, year: 2001, vol: 77, page: 628, stat: Journal Article,

Amyloid beta40/42 clearance across the blood-brain barrier following intra-ventricular injections in wild-type, apoE knock-out and human apoE3 or E4 expressing transgenic mice
Ji Y; Permanne B; Sigurdsson EM; Holtzman DM; Wisniewski T
2001 Feb;3(1):23-30, Journal of Alzheimer's Disease
An important event in the pathogenesis of Alzheimer's disease (AD) is the deposition of the amyloid beta (Abeta)1-40 and 1-42 peptides in a fibrillar form, with Abeta42 typically having a greater propensity to undergo this conformational change. A major risk factor for late-onset AD is the inheritance of the apolipoprotein E (apoE) 4 allele [3,14,31]. We previously proposed that apoE may function as a 'pathological chaperone' in the pathogenesis of AD (i.e. modulate the structure of Abeta, promoting or stabilizing a beta-sheet conformation), prior to the discovery of this linkage [7,40,41,42]. Data from apoE knockout / AbetaPP^(V717F) mice, has shown that the presence of apoE is necessary for cerebral amyloid formation [1,2], consistent with our hypothesis. However, in betaPP^(V717F) mice expressing human apoE3 or E4 early Abeta deposition at 9 months is suppressed, but by 15 months both human apoE expressing mice had significant fibrillar Abeta deposits with the apoE4 expressing mice having a 10 fold greater amyloid burden [8,9]. This and other data has suggested that apoE, in addition to having a facilitating role in fibril formation, may also influence clearance of Abeta peptides. In order to address if apoE affects the clearance of Abeta peptides across the blood-brain barrier (BBB) and whether there are differences in the clearance of Abeta40 versus Abeta42, we performed stereotactic, intra-ventricular micro-injections of Abeta40, Abeta42 or control peptides in wild-type, apoE knock-out (KO) or human apoE3 or apoE4 expressing transgenic mice. We found that consistent with other studies [5], Abeta40 is rapidly cleared from the brain across the BBB; however, Abeta42 is cleared much less effectively. This clearance of exogenous Abeta peptides across the BBB does not appear to be affected by apoE expression. This data suggests that Abeta42 production may favor amyloid deposition due to a reduced clearance across the BBB, compared to Abeta40. In addition, our experiments support a role of apoE as a pathological chaperone, and do not suggest an isotype specific role of apoE in exogenous Abeta peptide clearance from the CSF across the BBB
— id: 32921, year: 2001, vol: 3, page: 23, stat: Journal Article,

Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice
Sigurdsson EM; Scholtzova H; Mehta PD; Frangione B; Wisniewski T
2001 Aug;159(2):439-447, American journal of pathology
Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Abeta homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta fibrils
— id: 23485, year: 2001, vol: 159, page: 439, stat: Journal Article,

Immunization with a soluble and non-toxic amyloid-beta derivative substantially impedes Alzheimer's disease associated pathology in transgenic mice
Sigurdsson, E. M.; Schwaninger, J.; Scholtzova, H.; Mehta, P. D.; Ji, Y.; Ahlawat, S.; Sparks, C. M.; Quartermain, D.; Frangione, B.; Wisniewski, T.
2001 ;27(2):1807-447, Abstracts (Society for Neuroscience)
Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and it can seed fibril formation. We report that immunization in 11-12 months old Tg2576 APP mice for 7 months, with K6Abeta1-30, a highly soluble, non-amyloidogenic and non-toxic Abeta homologous peptide, reduced cortical and hippocampal brain amyloid burden by 89% (p=0.0002) and 81% (p=0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (p=0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice, indicating reduced inflammation in these animals. We are currently performing a long-term study on the histological, biochemical and behavioral effects of K6Abeta1-30 vaccination, where the mice received their first immunization at 2-4 months of age. Our preliminary results are that mice immunized with K6Abeta1-30 or Abeta1-42 in aluminum adjuvants have comparable titers although the former is much more soluble. Overall, our present findings suggest that immunization with soluble Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta aggregates
— id: 97635, year: 2001, vol: 27, page: 1807, stat: Journal Article,

Conformation as a therapeutic target in the prionoses and other neurodegenerative conditions
Wisniewski T; Sigurdsson EM; Aucouturier P; Frangione B
Molecular pathology of the prions Totowa NJ: Humana Press, 2001,
— id: 2638, year: 2001, vol: , page: ?, stat: Chapter,

Conformation as therapeutic target in the prionoses and other neurodegenerative conditions
Wisniewski, T; Sigurdsson, E M; Aucouturier, P; Frangione, B
2001 ;59:223-236, Methods in molecular medicine
Neurodegenerative conditions are increasing in prevalence as the average human life expectancy rises. Alzheimer's disease (AD) is the fourth commonest cause of death in the United States; the recent outbreak of new variant Creutzfeldt-Jakob disease (nvCJD) has raised the specter of a large population being at risk to develop this prionosis. The pathogenesis of many neurodegenerative diseases is now recognized to be associated with abnormalities of protein conformation. A common theme in these disorders is the conversion of a soluble normal precursor protein into an insoluble, aggregated, ?-sheet rich form that is toxic. In AD, a critical event is the conversion of the normal, soluble A? (sA?) peptide into fibrillar A?, within neuritic plaques and congophilic angiopathy (1). Similarly, in the prionoses, the central event is the conversion of the normal prion protein, PrPC, to PrPSc (2). An increased ?-sheet content characterizes both A? and PrPSc
— id: 126513, year: 2001, vol: 59, page: 223, stat: Journal Article,

Amyloid-beta injection in rat amygdala alters tau protein but not mRNA expression
Chambers CB; Sigurdsson EM; Hejna MJ; Lorens SA; Lee JM; Muma NA
2000 Mar;162(1):158-170, Experimental neurology
Previously we demonstrated local and distant changes in tau protein immunoreactivity reminiscent of those seen in Alzheimer's disease (AD) following a unilateral injection of amyloid-beta (Abeta)(25-35) into the rat amygdala. To explore the relevance of these findings to AD, we compared the effects of Abeta(1-42) to those of Abeta(25-35). Injections of both Abeta(1-42) and Abeta(25-35) into rat amygdala resulted in increased tau-2 immunolabeling in neurons. To determine whether these alterations were due to changes in the expression of tau, we measured tau protein expression by Western blotting and tau mRNA isoform expression by the reverse transcription-polymerase chain reaction in the amygdala, hippocampus, and cerebellum following a unilateral injection of Abeta(25-35) or vehicle into the amygdala. The levels of tau proteins were increased bilaterally in the amygdala of Abeta(25-35)- compared to vehicle-treated animals 8 and 16 days following treatment. The molecular weights of tau proteins were decreased in the Abeta(25-35)-treated (59-69 kDa) compared to the vehicle-treated (67-72 kDa) animals 8 days following treatment. There were no changes in tau mRNA expression in any brain region examined. In this model, just as in AD, there is an increase in tau protein levels without a change in tau mRNA expression, suggesting that Abeta peptides may influence tau protein stability in both the rat and the human brain
— id: 23486, year: 2000, vol: 162, page: 158, stat: Journal Article,

In vivo reversal of amyloid-beta lesions in rat brain
Sigurdsson EM; Permanne B; Soto C; Wisniewski T; Frangione B
2000 Jan;59(1):11-17, Journal of neuropathology & experimental neurology
Cerebral amyloid-beta (Abeta) deposition is central to the neuropathological definition of Alzheimer disease (AD) with Abeta related toxicity being linked to its beta-sheet conformation and/or aggregation. We show that a beta-sheet breaker peptide (iAbeta5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iAbeta5-induced disassembly prevented and/or reversed neuronal shrinkage caused by Abeta and reduced the extent of interleukin-1beta positive microglia-like cells that surround the Abeta deposits. These findings suggest that beta-sheet breakers, such as iAbeta5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing Abeta-related histopathology
— id: 8565, year: 2000, vol: 59, page: 11, stat: Journal Article,

In vivo disassembly of cerebral amyloid-beta (Abeta) deposits in rat brain
Sigurdsson, E. M.; Permanne, B.; Soto, C.; Wisniewski, T.; Frangione, B.
1999 ;25(1-2):1805-78, Abstracts (Society for Neuroscience)
— id: 97639, year: 1999, vol: 25, page: 1805, stat: Journal Article,

beta-sheet breaker peptides prevent the formation of amyloid-beta deposits
Soto C; Sigurdsson EM; Morelli L; Kumar RA; Saborio GP; Castano EM; Frangione B
Alzheimer's disease and related disorders Chichester, NY: Wiley, 1999,
— id: 2639, year: 1999, vol: , page: ?, stat: Chapter,

beta-sheet breaker peptides as potential therapy for Alzheimer's disease
Sigurdsson, EM; Morelli, L; Kumar, RA; Castano, EM; Frangione, B; Soto, C
1998 NOV ;1(1):S35-S36, Alzheimer's reports
— id: 98326, year: 1998, vol: 1, page: S35, stat: Journal Article,

Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer's therapy [see comments]
Soto C; Sigurdsson EM; Morelli L; Kumar RA; Castano EM; Frangione B
1998 Jul;4(7):822-826, Nature medicine
Inhibition of cerebral amyloid beta-protein deposition seems to be an important target for Alzheimer's disease therapy. Amyloidogenesis could be inhibited by short synthetic peptides designed as beta-sheet breakers. Here we demonstrate a 5-residue peptide that inhibits amyloid beta-protein fibrillogenesis, disassembles preformed fibrils in vitro and prevents neuronal death induced by fibrils in cell culture. In addition, the beta-sheet breaker peptide significantly reduces amyloid beta-protein deposition in vivo and completely blocks the formation of amyloid fibrils in a rat brain model of amyloidosis. These findings may provide the basis for a new therapeutic approach to prevent amyloidosis in Alzheimer's disease
— id: 7803, year: 1998, vol: 4, page: 822, stat: Journal Article,

Bilateral injections of amyloid-beta 25-35 into the amygdala of young Fischer rats: behavioral, neurochemical, and time dependent histopathological effects
Sigurdsson EM; Lee JM; Dong XW; Hejna MJ; Lorens SA
1997 Nov-Dec;18(6):591-608, Neurobiology of aging
To examine the time course of the histopathological effects of bilateral injections of amyloid-beta 25-35 (A beta) and to determine if these effects are associated with a reduction in choline acetyltransferase activity and behavioral impairments, we injected A beta (5.0 nmol) into the amygdala of young male Fischer rats. Control rats received vehicle infusions. For histological analysis, animals were sacrificed at 8, 32, 64, 96, and 128 days postoperatively (n = 21-33 per timepoint). A beta induced neuronal tau-2 staining in the right, but not the left amygdala and hippocampus. A beta also induced reactive astrocytosis and neuronal shrinkage within the right hippocampus and amygdala, respectively. As with tau-2, these same brain regions within the left hemisphere in the A beta-treated rats were significantly less affected. In addition, A beta appeared to induce microglial and neuronal interleukin-1beta staining. The histopathological effects of A beta peaked at 32 days postoperatively but were not associated with a reduction in amygdaloid choline acetyltransferase activity. In a separate experiment, behavioral effects of bilateral intra-amygdaloid injections of A beta were analyzed at 34-52 days postoperatively. In an open field test, the treatment groups differed only in the numbers of rears emitted (p = 0.016). There was no effect of A beta in the Morris water maze or in the acquisition and retention of a one-way conditioned avoidance response. These data suggest a laterality in the histopathological effects of A beta and that the effects of single injections are in part transient. These findings also suggest a direct association between plaque and tangle formation in Alzheimer's disease, and support the use of this rat model to screen drugs that may alter the initial pathological events associated with Alzheimer's disease, that occur before the manifestations of extensive behavioral impairments become evident
— id: 23487, year: 1997, vol: 18, page: 591, stat: Journal Article,

Laterality in the histological effects of injections of amyloid-beta 25-35 into the amygdala of young Fischer rats
Sigurdsson EM; Lee JM; Dong XW; Hejna MJ; Lorens SA
1997 Jun;56(6):714-725, Journal of neuropathology & experimental neurology
We have observed that single amyloid-beta 25-35 (A beta) injections (5.0 nmol) into the right amygdala of rats produce progressive cytoskeletal and astrogliotic reactions not only within the amygdala, but also in distal brain regions that project to the amygdala. To determine if these effects are potentiated by bilateral injections, we injected A beta (5.0 nmol) into the left and right amygdala of young male Fischer rats. Animals were sacrificed 32 days postoperatively. Bilateral infusions of A beta induced significant neuronal shrinkage, tau-2 neuronal staining, and reactive astrocytosis within the right amygdala and/or hippocampus, compared with vehicle-treated rats. Surprisingly, the same brain regions within the left hemisphere were significantly less affected even though no differences were observed between the left and right amygdala in the size of Congored-positive A beta deposits. Unilateral injections of A beta into the left amygdala led to significant histological changes in the right amygdala and hippocampus, but not in the same brain regions within the left hemisphere. These results suggest a laterality in the histopathological effects of A beta in male Fischer rats. Identification of the cause for the lateralized effect of A beta may prove valuable for understanding the etiology of Alzheimer disease and provide possible therapeutic strategies designed to slow the progression of the disease
— id: 23489, year: 1997, vol: 56, page: 714, stat: Journal Article,

Local and distant histopathological effects of unilateral amyloid-beta 25-35 injections into the amygdala of young F344 rats
Sigurdsson EM; Lorens SA; Hejna MJ; Dong XW; Lee JM
1996 Nov-Dec;17(6):893-901, Neurobiology of aging
To determine if amyloid-beta (A beta) induces tau-immunoreactivity (IR) and reactive astrocytosis in vivo, we injected A beta 25-35 (5.0 nmol) into the right amygdala of rats. At 8 days postinjection, the peptide induced tau-2 IR in neuronal cell bodies and processes ipsilaterally in the amygdala, cingulate cortex, and hippocampus. At 32 days postinjection, the intensity of tau-2 IR was greater than at 8 days in the amygdala and hippocampus, but not in the cingulate cortex. Induction of Alz-50 IR also was progressive but the morphology and distribution was different from tau-2 IR. Beaded fibers with occasional neuronal perikarya were visualized with Alz-50, and the IR was primarily observed in the ipsilateral amygdala. In addition, amygdaloid injections of A beta 25-35 induced reactive astrocytosis, particularly in the ipsilateral hippocampus at 32 days postoperatively. To our knowledge, this is the first study to show that in vivo injections of A beta 25-35 induce progressive transsynaptic cytoskeletal and astrogliotic reactions, that gradually spread from the area of injection to brain regions that have prominent efferent connections with that area. These findings also suggest a direct association between plaque and tangle formation in Alzheimer's disease
— id: 23488, year: 1996, vol: 17, page: 893, stat: Journal Article,

Visual processing in Alzheimer's Disease
Celesia GG; Villa AEP; Brigell M; Lee JM; Sigurdsson E
Alzheimer's and Parkinson's diseases New York: Plenum Press, 1995,
— id: 2637, year: 1995, vol: , page: 1, stat: Chapter,

Degenerative disease: Alzheimer's - beta-amyloid
Sigurdsson EM
1995 ;4:17-22, Meeting reports. CNS
— id: 23496, year: 1995, vol: 4, page: 17, stat: Journal Article,

beta-Amyloid 25-35 and/or quinolinic acid injections into the basal forebrain of young male Fischer-344 rats: behavioral, neurochemical and histological effects
Sigurdsson EM; Hejna MJ; Lee JM; Lorens SA
1995 Dec 14;72(1-2):141-156, Behavioural brain research
beta-Amyloid peptides have been shown to potentiate the neurotoxic effect of excitatory amino acids in vitro. In order to determine if this occurs in vivo, four experiments were performed. We injected beta-amyloid 25-35 (beta A 25-35) and/or quinolinic acid (QA) bilaterally into the ventral pallidum/substantia innominata (VP/SI) of rats. Control rats received vehicle infusions. A high dose of QA (75.0 nmol/3 microliters) increased open field activity and impaired spatial learning in the Morris water maze, but did not affect the acquisition of a one-way conditioned avoidance response. These changes were associated with histological evidence of neurotoxicity and a reduction in amygdaloid but not frontal cortical or hippocampal choline acetyltransferase (ChAT) activity. A lower dose of QA (37.5 nmol/3 microliters) produced no behavioral effects. It reduced amygdaloid ChAT activity to a lesser extent than the higher dose (15% vs. 29-37%), and caused less histological damage. beta A 25-35 (1.0 or 8.0 nmol/3 microliters) failed to produce behavioral, histological or neurochemical signs of toxicity. Neither dose of beta A 25-35 potentiated the effects of QA (37.5 nmol) on behavior or amygdaloid ChAT activity, and did not appear to increase the histological damage caused by QA. These results suggest that in vivo beta A 25-35 is not neurotoxic and does not potentiate the neurotoxicity of QA in the VP/SI. Further, the histological effects of a high dose of beta A 25-35 (8.0 nmol/3 microliters; a cavitation containing a Congo red positive proteinaceous material) are quite distinct from those produced by a high dose of QA (75.0 nmol/3 microliters; widespread neuronal loss and gliosis)
— id: 23490, year: 1995, vol: 72, page: 141, stat: Journal Article,