Martin Sadowski, M.D., Ph.D.

Hyperglycemia increases amyloid accumulation and exacerbates cerebrovascular pathology in alzheimer's disease model animals
Asuni A.; Duszczyk M.; Sadowski M.
2011 ;7(4 SUPPL 1):S515-S515, Alzheimer's & Dementia
Background: Hyperglycemia is a metabolic abnormality defining diabetes mellitus (DM). Misfolding and accumulation of abnormally conformed amyloid-s (As) and associated neurodegenerative cascades underpins Alzheimer's disease (AD) pathogenesis. Epidemiological studies have repeatedly demonstrated increased coincidence of AD pathology in DM patients, and the clinical course of AD is often hastened in subjects with concomitant DM. Despite these associations, it remains unclear how DM mechanistically impacts AD. We have focused on defining the relationship between hyperglycemia (hGly) and the As pathology in AD transgenic (Tg) animals. Methods: Chronic hGly was induced in male Thy-1-APPKM670/671NL/PS1L166PAD Tg mice by intraperitoneal injection of streptozotocin (STZ) (200mg/kg), which is selectively toxic to insulin-producing pancreatic s-cells. STZ or vehicle (n=8) were injected at the age of two months; prior to appearance of As plaques and cerebral amyloid angiopathy (CAA) in this model. Animals were given ad libitum access to food and water. Blood glucose levels were monitored monthly. At eight months, animals were sacrificed, their brains extracted and portioned for biochemical analysis and immunohistochemistry. Statistical analysis was performed using Mann-Whitney U test. Results: Average non-fasted blood glucose in hGly-Tg mice was 398625mg/dL compared to 159612mg/dL in normoglycemic (nGly)- Tg mice. Total Formic acid extracted As40 and As42 levels were significantly elevated by 28.8% and 17.1% (p < 0.05), respectively in hGly-Tg mice compared to age/sex matched nGly-Tg mice. Aggregated As-specific ELISA revealed that hGly-Tg mice had 50.1% (p < 0.01) increases in As oligomers compared to nGly-Tg mice. Morphometric analysis revealed significantly increased CAA load in hGly-Tg mice by 61.9%(p < 0.05), associated with increased incidence and severity of perivascular haemorrhages 75.8% (p < 0.01) compared to nGly-Tg mice. There was a non-statistically significant increase in hippocampal (19.1%) and neocortical (16.9%) As plaque load in hGly-Tg mice. Conclusions: Chronic hyperglycemia is strongly associated with exacerbation of As pathology in ADTg mice. Primarily aggravatingCAA,which is allied with increased damage to blood vessel integrity. It also promotes formation of As oligomers which enhances As toxicity. Efforts to elucidate the mechanistic relationship between chronic hyperglycemia and exacerbation of As misfolding and accumulation is under way
— id: 136963, year: 2011, vol: 7, page: S515, stat: Journal Article,

Pyridin-2-ylmethylamine derivatives as novel inhibitors of ab aggregation and toxicity
Asuni A.; Pankiewicz J.; Kuszczyk M.; Kevin Lin X.; Almassian B.; Sadowski M.
2011 ;7(4 SUPPL 1):S471-S472, Alzheimer's & Dementia
Background: Longstanding accumulation of a toxic and prone to self-aggregation s-amyloid peptide (As) in the brain is considered a leading pathological mechanism of Alzheimer's disease (AD). Our goal is to develop a bloodbrain barrier (BBB) permeable, small molecule inhibitor of the As aggregation into toxic oligomers and fibrils, which could attenuate accumulation and toxicity of As in brains of AD patients. Methods: Several libraries of compounds encompassing multi-aryl and heteroaryl groups were developed and screened for toxicity in SK-N-SH human neuroblastoma cells and against As aggregation using assays specifically designed to promote assembly of synthetic As into oligomers or fibrils. The neuroprotective effects of the lead compound on excitatory synapses were investigated in 18 day in vitro (DIV) primary hippocampal neuronal cultures. The pharmacokinetic profile, including bioavailability and BBB penetration, were established in mice following oral and intravenous administration using a combined liquid chromatographymass spectrometry (LC-MS) approach. Results: Our screen has identified the lead compound dubbed ARN 4261, [(E)-2-(pyridin-2-ylmethyleneamino) phenol;MW=198.2Da], which is not toxic and at low micromolar concentration shows strong effects against both oligomerization and fibrillization of synthetic As peptide. Treatment of primary hippocampal neurons exposed to As with ARN4261 restored loss of synaptic proteins expression caused by As oligomers. We have subsequently modified the structure of ARN 4261 producing ARN 2966 (2-[(pyridine-2-ylmethyl)-amino]-phenol) which shows comparable anti-aggregation potency to ARN 4261, but it is more stable in acidic environment, hence it is suitable for oral administration. Pharmacokinetic experiments in mice showed that t_1/2 of ARN 2966 is 6.13hr and 64.2% of orally administered dose is absorbed from the alimentary tract and passes the portal circulation. Preliminary studies show that ARN 2966 penetrates the BBB after oral and intravenous administration. Conclusions: Pyridin-2-ylmethylamine derivatives are a class of novel promising AD therapeutics. They are non toxic, have strong anti-As aggregation and neuroprotective properties and can be easily modified chemically for enhanced oral bioavailability and BBB penetration. Experiments in AD transgenic mice characterizing their effect on AD pathology in vivo are currently ongoing
— id: 136966, year: 2011, vol: 7, page: S471, stat: Journal Article,

Therapeutic anti-prion monoclonal antibody 6D11 facilitates prpsc degradation in prion cell culture model
Pankiewicz J.; Asuni A.; Kascak R.; Prelli F.; Kirshenbaum K.; Hom N.; Sadowski M.
2011 ;7(4 SUPPL 1):S661-S661, Alzheimer's & Dementia
Background: Conformational transformation of a cellular prion protein (PrP^C) into the misfolded, proteinase K (PK)-resistant and self-replicating conformer PrP^Sc is considered to be the main pathological mechanism of prionoses. We and others have demonstrated that treatment with anti-PrP monoclonal antibodies (Mabs) stops replication of PrP^Sc in prion infected cell lines and significantly delays the clinical onset of disease in prion infected mice. This research was conducted to elucidate the mechanism(s) determining therapeutic efficacy of Mabs, which remains unknown. Methods: The effects of anti-PrP Mab on kinetics of PrP^Sc disappearance were investigated in N2A murine neuroblastoma line infected with 22L prion strain (N2A/22L), and in N2A/22L transfected with siRNA targeting Prnp mRNA. Trafficking of Cy3-6D11 in N2A and N2A/22L was tracked by a time-lapse fluorescent microscopy. Effects of Mabs and 3F4 on PrP solubility were studied in N2A clones over-expressing wild-type (WT) human PrP and Gerstmann-Straussler-Scheinker (GSS) mutant with either valine (V) or methionine (M) at position 129. Results: Mab treatment of N2A/ 22L resulted in total disappearance of PrP^Sc within 48hr, with PrP^Sc t_{1/ 2}=10.7hr. Mab treatment was associated with initial reduction in the level of total PrP and its unglycosylated fraction, which subsequently increased at 48hr, when PrP^Sc was no longer observed. Transfection of N2A and N2A/22L with siRNA resulted in 50% reduction of the total PrP after 17hr and 19.5hr, respectively. PrP^Sc level was diminished by 50% after 10.7hr in siRNA transfected N2A/22L, whereas Mab co-treatment shortened PrP^Sc t_1/2 to 7hr. Massive intracellular penetration of Cy3-6D11 was observed in N2A/22L but not in N2A cells, indicating that directs surface expressed PrP^Sc for intracellular degradation. Treatment of N2A clones over-expressing WT-M129 and WT-V129 human PrP and A117V/ M129, A117V/V129, and F198S/V129 GSS mutants with Mabs 3F4 and increased the detergent soluble PrP fraction from two to five folds (p< 0.05). Conclusions: Anti-PrP Mabs appear to exert their therapeutic effect by promoting degradation of PrP^Sc, but they do not affect PrP production. Anti- PrP Mabs increase the solubility of PrP aggregates, which likely exerts a complementary effect in promoting PrP^Sc degradation
— id: 136960, year: 2011, vol: 7, page: S661, stat: Journal Article,

Apolipoprotein e isoform related clearance of amyloid-b by primary cortical astrocytes
Sanchez S.; Asuni A.; Sadowski M.
2011 ;7(4 SUPPL 1):S526-S526, Alzheimer's & Dementia
Background: Progressive accumulation of amyloid-s (As) in the brain is the hallmark of Alzheimer's disease (AD). Excess As assembles into toxicoligomers or fibrils, which became deposited in the form of plaques or vascular deposits. As no compelling evidences for age related increase in As production have been provided, it is likely that impairment of As clearance plays critical role in development of sporadic AD. Multiple pathways of As clearance include proteolytic, enzymatic degradation in the extracellular space, clearance of As through the blood brain barrier, or uptake and degradation by glial cells. Indeed, astrocytes take up As in a clathrin-caveolin- dynamin-independent endocytosis through endosomes with efficiency depending on As aggregation status. Astrocytesare also the main source of apolipoprotein E (apo E) in the central nervous system. Apo E in isoform specific fashion is associated with the risk for AD occurrence. In this study we characterized uptake and degradation of As by astrocytes derived from apo E targeted replacement (TR) transgenic mice expressing human apo E isoforms E2, E3, and E4, apo E-KO mice, and wild type mice. Methods: Primary cortical astrocytes were established from 1-2 day old pups. Cells were treated with 1 to 10 mM of synthetic As40 or As42 for 0 to 96hr. The effect of As on astrocyte metabolic integrity was determined using MTT assay. The uptake of As from the medium and clearance by astrocyteswere evaluated using western-blotting analyses of cell culture medium and celllysate samples respectively. Results: All tested astrocytes were capable of clearing As40 and As42 from the culture medium with stronger effect on As40. Analysis of lysates demonstrated a low accumulation of As40 inside astrocytes while significant amount of As42 was found inside all types of astrocytes, but less robust in apo E-KO. The intra-astrocytic accumulated As42 appears to be mainly oligomeric. MTT assay demonstrated that As42, but not As40, diminished metabolic activity of astrocytes. Conclusions: Astrocytes demonstrate great capacity of As uptake and degradation. The As uptake appears to be independent from of apo E isoformstatus. Excess of As42 oligomerizes and accumulates inside astrocytes resulting in their dysfunction as determined by MTT assays
— id: 136962, year: 2011, vol: 7, page: S526, stat: Journal Article,

Toward improving the diagnosis of Alzheimer's disease
Sadowski M.J.; Schaffer J.D.; Silfen E.
2010 ;54(1):50-61, Medicamundi
— id: 111553, year: 2010, vol: 54, page: 50, stat: Journal Article,

Circulating angiogenic cells and Alzheimer's disease: contribution of the bone marrow to the pathogenesis of the disease
Sadowski, Martin J
2010 Jan;19(4):1241-1243, Journal of Alzheimer's Disease
— id: 108801, year: 2010, vol: 19, page: 1241, stat: Journal Article,

Effects of memantine on cerebrospinal fluid biomarkers of neurofibrillary pathology
Glodzik, Lidia; De Santi, Susan; Rich, Kenneth E; Brys, Miroslaw; Pirraglia, Elizabeth; Mistur, Rachel; Switalski, Remigiusz; Mosconi, Lisa; Sadowski, Martin; Zetterberg, Henrik; Blennow, Kaj; de Leon, Mony J
2009 Nov;18(3):509-513, Journal of Alzheimer's Disease
Previous studies showed that memantine inhibits tau hyperphosphorylation in vitro. In this study, phosphorylated tau (P-tau) and total tau (T-tau) were measured before and after 6 month treatment with memantine in 12 subjects ranging from normal cognition with subjective memory complaints, through mild cognitive impairment to mild Alzheimer's disease. Thirteen non-treated individuals served as controls. Treatment was associated with a reduction of P-tau in subjects with normal cognition. No treatment effects were seen among impaired individuals, suggesting that longer treatment time may be necessary to achieve biomarker effect in this group
— id: 108783, year: 2009, vol: 18, page: 509, stat: Journal Article,

The effects of normal aging and ApoE genotype on the levels of CSF biomarkers for Alzheimer's disease
Glodzik-Sobanska, Lidia; Pirraglia, Elizabeth; Brys, Miroslaw; de Santi, Susan; Mosconi, Lisa; Rich, Kenneth E; Switalski, Remigiusz; Saint Louis, Leslie; Sadowski, Martin J; Martiniuk, Frank; Mehta, Pankaj; Pratico, Domenico; Zinkowski, Raymond P; Blennow, Kaj; de Leon, Mony J
2009 May;30(5):672-681, Neurobiology of aging
While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer's disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60+/-10 years, range 36-86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Abeta42/Abeta40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by varepsilon4 genotype interactions were found for P-tau231 (beta=1.82; p<0.05) and IP (beta=1.6; p<0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in varepsilon4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Abeta changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study
— id: 86778, year: 2009, vol: 30, page: 672, stat: Journal Article,

Anti-PrP Mab 6D11 suppresses PrP(Sc) replication in prion infected myeloid precursor line FDC-P1/22L and in the lymphoreticular system in vivo
Sadowski, Martin J; Pankiewicz, Joanna; Prelli, Frances; Scholtzova, Henrieta; Spinner, Daryl S; Kascsak, Regina B; Kascsak, Richard J; Wisniewski, Thomas
2009 May;34(2):267-278, Neurobiology of disease
The pathogenesis of prion diseases is related to conformational transformation of cellular prion protein (PrP(C)) into a toxic, infectious, and self-replicating conformer termed PrP(Sc). Following extracerebral inoculation, the replication of PrP(Sc) is confined for months to years to the lymporeticular system (LRS) before the secondary CNS involvement results in occurrence of neurological symptoms. Therefore, replication of PrP(Sc), in the early stage of infection can be targeted by therapeutic approaches, which like passive immunization have limited blood-brain-barrier penetration. In this study, we show that 6D11 anti-PrP monoclonal antibody (Mab) prevents infection on a FDC-P1 myeloid precursor cell line stably infected with 22L mouse adapted scrapie strain. Passive immunization of extracerebrally infected CD-1 mice with Mab 6D11 resulted in effective suppression of PrP(Sc) replication in the LRS. Although, a rebound of PrP(Sc) presence occurred when the Mab 6D11 treatment was stopped, passively immunized mice showed a prolongation of the incubation period by 36.9% (pb0.0001) and a significant decrease in CNS pathology compared to control groups receiving vehicle or murine IgG. Our results indicate that antibody-based therapeutic strategies can be used, even on a short-term basis, to delay or prevent disease in subjects accidentally exposed to prions
— id: 101114, year: 2009, vol: 34, page: 267, stat: Journal Article,

Prominent Neuroleptic Sensitivity in a Case of Early-onset Alzheimer Disease due to Presenilin-1 G206A Mutation
Cercy, Steven P; Sadowski, Martin J; Wisniewski, Thomas
2008 Sep;21(3):190-195, Cognitive & behavioral neurology
OBJECTIVE: We describe atypical motor and cognitive features in a case of familial Alzheimer disease (FAD) due to presenilin-1 (PS-1) mutation. BACKGROUND: Extrapyramidal signs (EPS) typically are a late-presenting feature of sporadic Alzheimer disease (AD), but relatively little data are available regarding EPS in FAD. METHOD: A 59-year-old, right-handed man of Caribbean-Hispanic descent underwent brain imaging studies, laboratory tests for AD, and serial neurologic and neuropsychologic evaluations. RESULTS: The patient presented with recent-onset delusional ideation associated with cognitive decline. Prominent EPS developed soon after initiation of an atypical neuroleptic agent. Neuropsychologic evaluation revealed global cognitive deficits; he was found to be a carrier of a PS-1 point mutation at position G206A. EPS resolved completely after discontinuing the neuroleptic agent and coincided with improved motor speed, set initiation, and verbal fluency. CONCLUSIONS: Severe neuroleptic sensitivity and associated deficits of cognitive speed occurred in response to a dopaminergic antagonist agent; both responded readily to withdrawal of the offending agent. Patients with PS-1 AD may be at substantially increased risk of neuroleptic-induced EPS. That feature underscores the heterogeneity of the FAD clinical phenotype
— id: 83107, year: 2008, vol: 21, page: 190, stat: Journal Article,

Prion Diseases
Sadowski M; Verma A; Wisniewski T
Neurology in clinical practice Philadelphia, PA : Butterworth-Heinemann/Elsevier, 2008,
— id: 4960, year: 2008, vol: , page: 1567, stat: Chapter,

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,

Preventing beta-amyloid fibrillization and deposition: beta-sheet breakers and pathological chaperone inhibitors
Wisniewski, Thomas; Sadowski, Martin
2008 ;9 Suppl 2:S5-S5, BMC Neuroscience
Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble beta-amyloid (sAbeta) to oligomeric, fibrillar Abeta. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Abeta aggregation, including beta-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology
— id: 91501, year: 2008, vol: 9 Suppl 2, page: S5, stat: Journal Article,

Disease modifying approaches for Alzheimer's pathology
Sadowski, Marcin; Wisniewski, Thomas
2007 ;13(19):1943-1954, Current pharmaceutical design
Alzheimer's disease (AD) is the most common age-associated neurodegenerative disease in the world. The major neuropathological features of AD are synaptic loss, neuronal loss, neurofibrillary tangles and the deposition of amyloid-beta (Abeta) as plaques and in cerebral blood vessels. Numerous Abeta targeting therapeutic approaches have been shown to prevent amyloid deposition and resulting in cognitive improvement in transgenic mouse models of AD. Some of these approaches are currently in early clinical trials. It remains to be seen if these approaches will be proven effective in patients. Future anti-AD therapies will likely be multi-modal and individually tailored depending on the patient's immune status, genetic background and their amyloid burden, as determined by imaging studies using Abeta specific labeling ligands. Pre-clinical data suggests that it will be much more feasible to prevent AD related pathology, then to clear existing pathology, making early diagnosis critically important.
— id: 73005, year: 2007, vol: 13, page: 1943, stat: Journal Article,

Therapeutic monoclonal antibodies for prion exposure prophylaxis
Sadowski, MJ; Pankiewicz, J; Prelli, F; Scholtzova, H; Spinner, D; Kascsak, RB; Kascsak, RJ; Wisniewski, T
2007 ;68(12):A141-A142, Neurology
— id: 97601, year: 2007, vol: 68, page: A141, 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,

Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment
de Leon, M J; DeSanti, S; Zinkowski, R; Mehta, P D; Pratico, D; Segal, S; Rusinek, H; Li, J; Tsui, W; Saint Louis, L A; Clark, C M; Tarshish, C; Li, Y; Lair, L; Javier, E; Rich, K; Lesbre, P; Mosconi, L; Reisberg, B; Sadowski, M; DeBernadis, J F; Kerkman, D J; Hampel, H; Wahlund, L-O; Davies, P
2006 Mar;27(3):394-401, Neurobiology of aging
The diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) is limited because it is based on non-specific behavioral and neuroimaging findings. The lesions of Alzheimer's disease: amyloid beta (Abeta) deposits, tau pathology and cellular oxidative damage, affect the hippocampus in the earlier stages causing memory impairment. In a 2-year longitudinal study of MCI patients and normal controls, we examined the hypothesis that cerebrospinal fluid (CSF) markers for these pathological features improve the diagnostic accuracy over memory and magnetic resonance imaging (MRI)-hippocampal volume evaluations. Relative to control, MCI patients showed decreased memory and hippocampal volumes and elevated CSF levels of hyperphosphorylated tau and isoprostane. These two CSF measures consistently improved the diagnostic accuracy over the memory measures and the isoprostane measure incremented the accuracy of the hippocampal volume achieving overall diagnostic accuracies of about 90%. Among MCI patients, over 2 years, longitudinal hippocampal volume losses were closely associated with increasing hyperphosphorylated tau and decreasing amyloid beta-42 levels. These results demonstrate that CSF biomarkers for AD contribute to the characterization of MCI
— id: 62680, year: 2006, vol: 27, page: 394, stat: Journal Article,

Clearance and prevention of prion infection in cell culture by anti-PrP antibodies
Pankiewicz, Joanna; Prelli, Frances; Sy, Man-Sun; Kascsak, Richard J; Kascsak, Regina B; Spinner, Daryl S; Carp, Richard I; Meeker, Harry C; Sadowski, Marcin; Wisniewski, Thomas
2006 May;23(10):2635-2647, European journal of neuroscience
Prion diseases are transmissible and invariably fatal neurodegenerative disorders associated with a conformational transformation of the cellular prion protein (PrP(C)) into a self-replicating and proteinase K (PK)-resistant conformer, scrapie PrP (PrP(Sc)). Humoral immunity may significantly prolong the incubation period and even prevent disease in murine models of prionoses. However, the mechanism(s) of action of anti-PrP monoclonal antibodies (Mabs) remain(s) obscure. The murine neuroblastoma N2a cell line, infected with the 22L mouse-adapted scrapie strain, was used to screen a large library of Mabs with similar binding affinities to PrP, to identify those antibodies which could clear established infection and/or prevent infection de novo. Three Mabs were found capable of complete and persistent clearing of already-infected N2a cells of PrP(Sc). These antibodies were 6D11 (generated to PK-resistant PrP(Sc) and detecting PrP residues 93-109), and 7H6 and 7A12, which were raised against recombinant PrP and react with neighbouring epitopes of PrP residues 130-140 and 143-155, respectively. Mabs were found to interact with PrP(Sc) formation both on the cell surface and after internalization in the cytosol. Treatment with Mabs was not associated with toxicity nor did it result in decreased expression of PrP(C). Both preincubation of N2a cells with Mabs prior to exposure to 22L inoculum and preincubation of the inoculum with Mabs prior to infecting N2a cells resulted in a significant reduction in PrP(Sc) levels. Information provided in these studies is important for the rational design of humoral immune therapy for prion infection in animals and eventually in humans
— id: 65120, year: 2006, vol: 23, page: 2635, stat: Journal Article,

Apolipoproteins in different amyloidoses
Sadowski M; Wisniewski T
Protein misfolding, aggregation, and conformational diseases. Part A. Protein aggretation and conformational diseases New York : Springer, 2006,
— id: 4979, year: 2006, vol: , page: 329, stat: Chapter,

Characterization of therapeutically effective monoclonal antibodies against prion protein
Sadowski, M; Pankiewicz, J; Prelli, F; Sy, MS; Kascsak, RJ; Kascsak, RB; Spinner, DS; Carp, RI; Meeker, HC; Wisniewski, T
2006 ;66(5):A258-A258, Neurology
— id: 97603, year: 2006, vol: 66, page: A258, stat: Journal Article,

Inhibition the apolipoprotein E/amyloid-beta interaction as a novel therapeutic approach for Alzheimer's disease
Sadowski, M; Pankiewicz, J; Scholtzova, H; Wen, P; Mehta, P; Quartermain, D; Wisniewski, T
2006 ;66(5):A379-A379, Neurology
— id: 97604, year: 2006, vol: 66, page: A379, stat: Journal Article,

Blocking the apolipoprotein E/amyloid-{beta} interaction as a potential therapeutic approach for Alzheimer's disease
Sadowski, Martin J; Pankiewicz, Joanna; Scholtzova, Henrieta; Mehta, Pankaj D; Prelli, Frances; Quartermain, David; Wisniewski, Thomas
2006 Dec 5;103(49):18787-18792, Proceedings of the National Academy of Sciences of the United States of America
The amyloid-beta (Abeta) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of Abeta peptide constitutes a critical event in the early disease pathogenesis. The direct binding between Abeta and apolipoprotein E (apoE) is an important factor implicated in both Abeta clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/Abeta interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed Abeta12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length Abeta. Abeta12-28P binds with high affinity to apoE, preventing its binding to Abeta, but has no direct effect on Abeta aggregation. Abeta12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of Abeta plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of Abeta in two AD transgenic mice models. The treatment did not affect the levels of soluble Abeta fraction or Abeta oligomers, indicating that inhibition of the apoE/Abeta interaction in vivo has a net effect of increasing Abeta clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with Abeta12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD
— id: 69282, year: 2006, vol: 103, page: 18787, stat: Journal Article,

Characterization and non-invasive imaging of lens b-amyloid in the Tg2576 mouse model of Alzheimer's disease
Goldstein, LE; Moir, R; Arnett, E; Sadowski, M; Tanzi, R; Wisniewski, T; Klunk, W; Clark, J; Chylack, LT
2005 ;46(Suppl. S):2905-A379, Investigative ophthalmology & visual science. IOVS
— id: 97605, year: 2005, vol: 46, page: 2905, stat: Journal Article,

Anti-PrP monoclonal antibodies for prevention of prion infection
Pankiewicz, J; Prelli, F; Sadowski, M; Scholtzova, H; Kascsak, R; Kascsak, R; Carp, RI; Meeker, CH; Sy, MS; Wisniewski, T
2005 ;64(6):A249-A250, Neurology
— id: 97606, year: 2005, vol: 64, page: A249, stat: Journal Article,

MRI approaches for specific targeting of PrPSc in the spleen of prion infected presymptomatic subjects
Sadowski, M; Wadghiri, ZY; Brown, D; Scholtzova, H; Pankiewicz, J; Turnbull, DH; Wisniewski, T
2005 ;64(6):A409-A410, Neurology
— id: 97607, year: 2005, vol: 64, page: A409, stat: Journal Article,

Therapeutics and prion disease: Can immunisation or drugs be effective?
Sassoon, J; Sadowski, M; Wisniewski, T; Brown, DR
2005 APR ;5(4):361-366, Mini reviews in medicinal chemistry
Prion diseases are of considerable importance because of the threat of a variant form of Creutzfeldt Jakob disease that has emerged in recent years. Pre-clinical diagnosis of prion diseases still remains poor and effective therapies also do not exist at present. This review examines research on possible therapeutic strategies that might have potential benefits if applied before neurodegeneration has occurred
— id: 50153, year: 2005, vol: 5, page: 361, 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,

Prion diseases
Sadowski M; Verma A; Wisniewski T
Neurology in clinical practice Philadelphia : Butterworth-Heinemann, 2004,
— id: 3167, year: 2004, vol: , page: 1613, stat: Chapter,

100 questions and answers about Alzheimer's disease
Sadowski M; Wisniewski T
Boston : Jones & Bartlett, 2004,
— id: 763, year: 2004, vol: , page: , stat: ,

Blocking the apolipoprotein E/beta-amyloid interaction by synthetic peptide mitigates beta-amyloid toxicity and fibril formation in vitro and in vivo
Sadowski, M; Pankiewicz, J; Scholtzova, H; Li, Y; Sigurdsson, EM; Wisniewski, T
2004 AUG ;13(3):237-237, Protein science
— id: 55684, year: 2004, vol: 13, page: 237, stat: Journal Article,

In vivo imaging of prion amyloid deposits
Sadowski, M; Pankiewicz, J; Scholtzova, H; Tsai, J; Carp, RI; Meeker, HC; Debnath, M; Mathis, CA; Shao, L; Klunk, WE; Gan, WB; Wisniewski, T
2004 JUL ;25(10):S280-S281, Neurobiology of aging
— id: 47732, year: 2004, vol: 25, page: S280, stat: Journal Article,

Specific detection of PrPSc in the spleens of prion infected, presymptomatic mice by MRI
Sadowski, M; Wadghiri, YZ; Brown, D; Pankiewicz, J; Scholtzova, H; Tang, CY; Turnbull, DH
2004 JUL ;25(10):S465-S465, Neurobiology of aging
— id: 47741, year: 2004, vol: 25, page: S465, stat: Journal Article,

Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Ji, Yong; Quartermain, David; Jensen, Catrin H; Duff, Karen; Nixon, Ralph A; Gruen, Rand J; Wisniewski, Thomas
2004 May;63(5):418-428, Journal of neuropathology & experimental neurology
In Alzheimer disease (AD) patients, early memory dysfunction is associated with glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double 'Swedish' amyloid precursor protein (APP) mutations, are a model of AD amyloid-beta deposition (Abeta) that exhibits earlier and more profound impairments of working memory and learning than single APP mutant mice. In this study we compared performance on spatial memory tests, regional glucose metabolism, Abeta deposition, and neuronal loss in APP/PS1, PS1, and non-Tg (nTg) mice. At the age of 2 months no significant morphological and metabolic differences were detected between 3 studied genotypes. By 8 months, however, APP/PS1 mice developed selective impairment of spatial memory, which was significantly worse at 22 months and was accompanied by reduced glucose utilization in the hippocampus and a 35.8% dropout of neurons in the CA1 region. PS1 mice exhibited a similar degree of neuronal loss in CA1 but minimal memory deficit and no impairment of glucose utilization compared to nTg mice. Deficits in 22 month APP/PS1 mice were accompanied by a substantially elevated Abeta load, which rose from 2.5% +/- 0.4% at 8 months to 17.4% +/- 4.6%. These findings implicate Abeta or APP in the behavioral and metabolic impairments in APP/PS1 mice and the failure to compensate functionally for PS1-related hippocampal cell loss
— id: 44514, year: 2004, vol: 63, page: 418, stat: Journal Article,

Links between the pathology of Alzheimer's disease and vascular dementia
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Li, Yong-sheng; Quartermain, David; Duff, Karen; Wisniewski, Thomas
2004 Jul;29(6):1257-1266, Neurochemical research
The major neuropathological lesions defining Alzheimer's disease (AD) include neurofibrillary tangles and amyloid plaques, which are mainly composed of abnormally phosphorylated tau and amyloid-beta (A beta), respectively. Numerous neuropathological and neuroimaging studies indicate that at least one-third of AD cases are complicated by some degree of vascular pathology, whereas in a similar proportion of patients clinically diagnosed with vascular dementia, AD pathology is also present. Many classical vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have recently been shown also to increase the risk of AD. Growing evidence suggests that vascular pathology lowers the threshold for the clinical presentation of dementia at a given level of AD-related pathology and potentially directly promotes AD lesions such as A beta plaques. Cerebral ischemia, chronically up-regulates expression of the amyloid precursor protein (APP), which is the precursor to the amyloid beta peptide and damages the blood-brain barrier (BBB), affecting A beta peptide clearance from the brain. Recognition of the importance of these vascular risk factors for AD-related dementia and their treatment will be beneficial not only for preventing cardiac, cerebral, and peripheral complications of vascular disease, but also will likely have a direct impact on the occurrence of sporadic AD in older subjects. In this paper, we review some of the links between vascular risk factors and AD pathology and present data on the direct effect of ischemia on cognitive function and A beta deposition in a mouse model of AD
— id: 46031, year: 2004, vol: 29, page: 1257, 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,

Detection of prion amyloid deposits in vivo
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Tsai, Julia; Carp, Richard I.; Meeker, Cliff H.; Gan, Wen-Biao; Klunk, William E.; Mathis, Chester A.; Shao, Li; Debnath, Manik; Wisniewski, Thomas
2004 ;62(7, Suppl. 5):A446-A447, Neurology
— id: 97609, year: 2004, vol: 62, page: A446, stat: Journal Article,

Targeting prion amyloid deposits in vivo
Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Tsai, Julia; Li, Yongsheng; Carp, Richard I; Meeker, Harry C; Gambetti, Pierluigi; Debnath, Manik; Mathis, Chester A; Shao, Li; Gan, Wen-Biao; Klunk, William E; Wisniewski, Thomas
2004 Jul;63(7):775-784, Journal of neuropathology & experimental neurology
The diagnosis of prion diseases in humans is challenging due to a lack of specific and sensitive non-invasive tests. Many forms of human prion disease including variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Straussler-Scheinker (GSS) syndrome, and 10% of sporadic CJD cases are associated with amyloid deposition. Several positron emission tomography (PET) ligands have recently been developed to directly image beta-amyloid associated with Alzheimer disease. One of them, methoxy-X04, is a fluorescent derivative of Congo red with high binding affinity toward amyloid fibrils and good blood-brain barrier permeability. Using methoxy-X04, we investigated whether amyloid-targeting ligands can be also employed for direct imaging of amyloid deposits associated with some prion diseases. Such a method could potentially become a novel diagnostic approach for these conditions. Studies were performed on MB mice infected with the 87V mouse-adapted scrapie strain. Labeling of PrP amyloid plaques in brains of presymptomatic and symptomatic mice was demonstrated using in vivo transcranial two-photon microscopy after systemic administration of methoxy-X04. During real-time imaging, PrP amyloid deposits could be clearly distinguished 15 min after intravenous administration of methoxy-X04. The ligand showed rapid clearance from brain areas that did not contain amyloid deposits. PrP amyloid deposits could also be detected by direct application of methoxy-X04 on cerebellar sections from GSS patients. These results suggest that methoxy-X04 or similar derivatives could be used as PET imaging agents to improve the diagnosis of human prion diseases associated with amyloid deposition
— id: 44512, year: 2004, vol: 63, page: 775, stat: Journal Article,

Vaccines for conformational disorders
Sadowski, Marcin; Wisniewski, Thomas
2004 ;3(3):279-90, Expert review of vaccines
Neurodegenerative disorders are becoming increasingly common and an ever greater healthcare burden, as the average age in Western populations rises. Many of these are conformational disorders, which are characterized by the accumulation of a host protein that undergoes a structural change increasing its beta-sheet content, rendering it toxic. The most common of these illnesses is Alzheimer's disease. Prion diseases are also conformational disorders, which are currently less common than Alzheimer's disease, however, these illnesses have no treatment and are universally rapidly fatal. The emergence of new variant Creutzfeldt-Jakob disease has raised the possibility of a large population at risk for this illness, as well as causing great concern regarding the safety of blood bank supplies. Recently, immune modulation has emerged as a highly promising therapeutic strategy for both Alzheimer's and prion diseases. We and others have demonstrated in both Alzheimer's and prion disease animal models that vaccination can dramatically improve the course of the illness. A human trial of an Alzheimer's disease vaccine using A beta1-42 was halted due to toxicity in a minority of patients (6%). However, recent data suggests that patients with a humoral response to A beta benefited cognitively from the vaccine. Toxicity in this human trial has been linked to excessive cell-mediated immunity. Novel vaccine strategies are under development for both Alzheimer's disease and prionoses which are predicted to have few or no significant side effects, while being efficacious. $$:
— id: 97608, year: 2004, vol: 3, page: 279, stat: Journal Article,

Age-associated behavioral, metabolic, and structural changes in wild-type littermates of Alzheimer's transgenic mice
Scholtzova, H; Pankiewicz, J; Sadowski, M; Quartermain, D; Jensen, CH; Duff, K; Nixon, RA; Helpern, JH; Gruen, RJ; Wisniewski, T
2004 JUL ;25(10):S225-S226, Neurobiology of aging
— id: 47726, year: 2004, vol: 25, page: S225, 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,

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,

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,

Global ischemia exacerbates Alzheimer's disease related pathology in transgenic mice
Pankiewicz, J.; Scholtzova, H.; Sadowski, M.; Ferris, S.; Li, Y. S.; Quartermain, D.; Duff, K.; Wisniewski, T.
2003 ;2003(7, Suppl. 5):Abstract No. 534.7-S583, Society for Neuroscience Abstract Viewer & Itinerary Planner
A significant percentage of Alzheimer's disease (AD) patients exhibit concomitant vascular pathology. Epidemiological evidence suggest that vascular disease may not only add to global cognitive impairment but also exacerbate the course of AD pathology. The goal of this study was to analyze the impact of global ischemia on the cellular and amyloid-beta pathology in AD murine transgenic (Tg) models. Seven month old double Tg mice, expressing Swedish amyloid precursor protein (APP) and M146L presenilin 1 (PS1) mutations and single Tg mice (PS1 mutation alone) were subjected to 45 minutes bilateral common carotid artery occlusion or sham surgery. Behavioral testing performed two weeks after the surgery showed impaired learning and memory retention on Morris water maze and Hebb-Williams tests in both single PS1 and double PS1/APP Tg mice which underwent ischemia comparing to sham operated animals (p<0.05). Double Tg mice scored worse than single Tg mice. Animals were sacrificed two months after ischemia. The total brain volume was decreased by 6.5% and 5% and the ventricular volume was increased by 33.7% and 46.4% in single and double operated Tg mice, respectively comparing to sham animals. Unbiased stereological analysis demonstrated a 23% neuronal dropout in the CA1 sector of the cornu Ammonis after ischemia. Increased Abetaburden and plaque density was also observed in APP/PS1 animals which underwent ischemia comparing to sham operated ones. Overall, this data indicate that global ischemia exacerbate both neuronal and Abetarelated pathology in AD Tg animal models
— id: 97611, year: 2003, vol: 2003, page: Abstract No. 534.7, 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,

Behavioral and metabolic abnormalities in APP/PSI transgenic mice
Sadowski, M; Pankiewicz, J; Scholtzova, H; Quartermain, D; Jensen, C; Gruen, RJ; Duff, K; Nixon, RA; Wisnicwski, T
2003 MAY ;62(5):549-549, Journal of neuropathology & experimental neurology
— id: 38569, year: 2003, vol: 62, page: 549, 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,

MRI approaches for the detection of prion disease pathology
Sadowski, Marcin; Tang, Cheuk Ying; Aguinaldo, Gilbert; Carp, Richard; Wadghiri, Youssef Zaim; Turnbull, Daniel H.; Wisniewski, Thomas
2003 ;60(5 Supplement 1):A250-118, Neurology
— id: 97614, year: 2003, vol: 60, page: A250, stat: Journal Article,

In vivo micro magnetic resonance imaging signal changes in scrapie infected mice
Sadowski, Marcin; Tang, Cheuk Ying; Aguinaldo, Juan Gilberto; Carp, Richard; Meeker, Harry C; Wisniewski, Thomas
2003 Jul 10;345(1):1-4, Neuroscience letters
Signal abnormalities on magnetic resonance imaging (MRI) T2-weighted images (T2WI) have been described in patients with Creutzfeldt-Jakob disease; however, the pathology underlying these findings remains to be fully described. We investigated the time-course of signal alterations in a murine model of prion disease using in vivo 9.4 Tesla micro magnetic resonance imaging (muMRI). The topography of muMRI signal changes was correlated with the accumulation of proteinase resistant PrP(Sc) in corresponding brain sections. Increased signal intensity on T2WI was observed in the septum and in the hippocampus of presymptomatic mice 120 days post infection (dpi). Mildly symptomatic animals (150 dpi) and animals with apparent neurological deficit (180 dpi) had a greater increase of signal intensity on T2WI in the septum and the hippocampus; in addition, abnormalities in the cortex and in the thalamus were found. Neuropathological evaluation demonstrated accumulation of PrP(Sc) and astrogliosis but only minimal or no spongiform changes in structures where abnormal signal was detected. These observations suggest that early pathological changes related to the accumulation of PrP(Sc) may be detectable in presymptomatic subjects using MRI systems with higher magnetic field strength
— id: 38796, year: 2003, vol: 345, page: 1, stat: Journal Article,

Immunological therapeutic and imaging approaches for prion disease
Sadowski, Marcin; Wisniewski, Thomas
2003 ;3(2):113-118, Current medicinal chemistry: Immunology, endocrine & metabolic agents
— id: 97612, year: 2003, vol: 3, page: 113, stat: Journal Article,

Mice expressing presenilin - 1 mutations demonstrate age - related neuronal loss
Scholtzova, H.; Pankiewicz, J.; Sadowski, M.; Li, Y. S.; Quartermain, D.; Wen, P. H.; Elder, G.; Duff, K.; Wisniewski, T.
2003 ;2003(5 Supplement 1):Abstract No. 729.8-118, Society for Neuroscience Abstract Viewer & Itinerary Planner
Presenilin 1 (PS1) mutations have been identified in many pedigrees with early-onset familial Alzheimer's disease (FAD). PS1 mutants are known to influence gamma-secretase action and increase amyloid-beta (Abeta) 1-42 production, but there is also evidence suggesting direct involvement of PS1 in the neuronal pathology of AD. Transgenic (Tg) mice expressing the M146L PS1 mutation, associated with FAD symptom onset in the forties, demonstrate no difference in the total number of neurons (fractionator method) in the CA1 sector of the cornu Ammonis comparing with wild type (wt) animals at two months of age. At the age of 9 months and 22 months PS1 M146L Tg mice demonstrated 20% and 29% neuronal dropout comparing to age-matched controls, respectively (p<0.05). Between 2 months and 22 months old wt animals did not show any significant neuronal loss; however, 22 month old M146L PS1 mice showed a 41% neuronal decline compared to 2 month old controls. PS1 M146L Tg animals also exhibited impaired performance of both learning and retention on the Morris water maze test (p<0.05), but not on locomotor testing comparing to wt mice. We have also analyzed another line of Tg mice expressing a P117L PS1 mutation associated with an onset of disease as early as 23 years. These mice at the age of 6 months demonstrate a 17.9% reduction in the total number of CA1 neurons comparing to wt mice and a 26.5% reduction comparing to mice expressing the wt form of human PS1 (p<0.05). Overall, this data suggest that PS1 mutations are directly involved in neuronal pathology which is age-dependant. This process is unrelated to Abeta deposition since PS1 Tg mice do not develop amyloid plaques
— id: 97616, year: 2003, vol: 2003, page: Abstract No. 729.8, stat: Journal Article,

Ex - vivo magnetic resonance imaging of beta - amyloid plaques in transgenic AD mice
Tang, C.; Hajianpour, A.; Aguinaldo, G.; Ho, L.; Pasinetti, G.; Hof, P. R.; Perl, D. P.; Sadowski, M.; Wisniewski, T.
2003 ;2003(5 Supplement 1):Abstract No. 862.3-118, Society for Neuroscience Abstract Viewer & Itinerary Planner
According to the amyloid hypothesis, it is the progressive accumulation of beta-amyloid that leads to a cascade of neurodegenerative processes in Alzheimer's disease (AD). Thus, current strategies for diagnosis and treatment evaluation rely on the ability to accurately quantify beta-amyloid burden. It has previously been shown that beta-amyloid plaques can be imaged using Magnetic Resonance Microscopy (MRM) at 40mum isotropic resolution in ex vivo human samples of the hippocampus. Transgenic (Tg) mice have been generated for research as beta-amyloidosis models. Plaque sizes range can from 5mum to 200mum, with an average diameter of approximately 25mum. In the present study, we used high resolution MRM to explore the feasibility of visualizing beta-amyloid plaque deposits in the brain of Tg2576 mice carrying the Swedish mutation of APP. We obtained T2 weighted 3D whole brain MRM data at 20mum and 25mum isotropic resolution. MRM images were compared with histological data to confirm that the signal seen on MRM corresponded to actual beta-amyloid plaque deposits. We conclude that MRM is a practical and useful assay for imaging beta-amyloid plaques with diameters as small as 20mum. These results will aid in the interpretation of MRI data gathered from in-vivo scans of mice, including scans wherein contrast agents are employed. This MRI technique can be easily applied to whole brain plaque quantification studies and for the purpose of studying treatment strategies using mouse models of AD, and may further be extended to in vivo studies tracking amyloid deposit formation and maturation throughout the animals life span
— id: 97617, year: 2003, vol: 2003, page: Abstract No. 862.3, 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,

Long-term changes in calbindin D(28K) immunoreactivity in the rat hippocampus after cardiac arrest
Sadowski, Marcin; Lazarewicz, Jerzy W; Jakubowska-Sadowska, Katarzyna; Wisniewski, Henryk M; Mossakowski, Miroslaw J; Brown, W Ted
2002 Mar 15;321(1-2):90-94, Neuroscience letters
Calbindin D(28K) (CB) expression was analyzed in the rat hippocampus following 10-min-cardiac arrest-induced ischemia within a year after reperfusion. In rats examined 3 days after ischemia, CB immunoreactivity disappeared completely from CA1 pyramidal neurons and from most CA2 pyramids. In the stratum granulosum of the dentate gyrus, mossy fibers, and hippocampal interneurons, CB immunoreactivity was preserved, although staining was somewhat paler than that in control rats. A similar pattern of CB immunoreactivity was found in rats sacrificed 14 days and 1 month after cardiac arrest. From the 14th postischemic day, neuronal loss in the stratum pyramidale of CA1 but not in that of CA2 became apparent. The reappearance of CB immunoreactivity in CA1 and CA2 pyramidal neurons was noticed 6 months after ischemia, and the pattern was identical to that observed in animals sacrificed 12 months after the ictus. The prolonged loss and delayed reappearance of CB immunoreactivity in the hippocampus demonstrate that ischemia may induce long-term disturbances of protein expression, which may in turn result in impairment of hippocampal functioning
— id: 32843, year: 2002, vol: 321, page: 90, stat: Journal Article,

Effect of the presenilin 1 P117L FAD linked mutation on hippocampal morphology transgenic mice
Sadowski, M; Wen, PH; Elder, GA; Robakis, NK; Wisniewski, T
2001 MAY ;60(5):543-543, Journal of neuropathology & experimental neurology
— id: 55071, year: 2001, vol: 60, page: 543, stat: Journal Article,

Pattern of neuronal loss in the rat hippocampus following experimental cardiac arrest-induced ischemia
Sadowski M; Wisniewski HM; Jakubowska-Sadowska K; Tarnawski M; Lazarewicz JW; Mossakowski MJ
1999 Sep 15;168(1):13-20, Journal of the neurological sciences
The pattern of neuronal loss in the rat hippocampus following 10-min-long cardiac arrest-induced global ischemia was analyzed using the unbiased, dissector morphometric technique and hierarchical sampling. On the third day after ischemia, the pyramidal layer of sector CA1 demonstrated significant (27%) neuronal loss (P<0.05). At this time, no neuronal loss was observed in other cornu Ammonis sectors or the granular layer of the dentate gyrus. On the 14th postischemic day, further neuronal loss in the sector CA1 pyramidal layer was noticed. At this time, this sector contained 31% fewer pyramidal neurons than on the third day (P<0.05) and 58% fewer than in the control group (P<0.01). On the 14th day, neuronal loss in other hippocampal subdivisions also was observed. The pyramidal layer of sector CA3 contained 36% fewer neurons than in the control group (P<0.05), whereas the granular layer of the dentate gyrus contained 40% fewer (P<0.05). The total number of pyramidal neurons in sector CA2 remained unchanged. After the 14th day, no significant alterations in the total number of neurons were observed in any subdivision of the hippocampus until the 12th month of observation. Unbiased morphometric analysis emphasizes the exceptional susceptibility of sector CA1 pyramidal neurons to hypoxia/ischemia but also demonstrates significant neuronal loss in sector CA3 and the dentate granular layer, previously considered 'relatively resistant'. The different timing of neuronal dropout in sectors CA1 and CA3 and the dentate gyrus may implicate the existence of region-related properties, which determine earlier or later reactions to ischemia. However, the hippocampus has a unique, unidirectional system of intrinsic connections, whereby the majority of dentate granular neuron projections target the sector CA3 pyramidal neurons, which in turn project mostly to sector CA1. As a result, the early neuronal dropout in sector CA1 may result in retrograde transynaptic degeneration of neurons in other areas. The lack of neuronal loss in sector CA2 can be explained by the resistance of this sector to ischemia/hypoxia and the fact that this sector is not included in the major chain of intrahippocampal connections and hence is not affected by retrograde changes
— id: 32844, year: 1999, vol: 168, page: 13, stat: Journal Article,

Entorhinal cortex of aged subjects with Down's syndrome shows severe neuronal loss caused by neurofibrillary pathology
Sadowski M; Wisniewski HM; Tarnawski M; Kozlowski PB; Lach B; Wegiel J
1999 Feb;97(2):156-164, Acta neuropathologica
In Alzheimer's disease (AD), neurofibrillary degeneration of neurons starts in the transentorhinal cortex and spreads in a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus--a key structure of the memory system. People with Down's syndrome (DS) develop neurofibrillary changes more than 30 years earlier than those with sporadic AD. To characterize AD-related pathology in the entorhinal cortex in DS, we examined seven subjects with DS of 60-74 years of age who died in the end stage of AD, and four age-matched control subjects. The volume of the entorhinal cortex in brains of subjects with DS was 42% less than that in control cases; however, the total number of neurons free of neurofibrillary changes was reduced in DS by 90%: from 9,619,000 +/- 914,000 (mean +/- standard deviation) to 932,000 +/- 504,000. The presence of 2,488,000 +/- 544,000 neurofibrillary tangles in the entorhinal cortex of people with DS, the prevalence of end-stage tangles, and the significant negative correlation between the total number of intact neurons and the percentage of neurons with neurofibrillary changes indicate that neurofibrillary degeneration is a major cause of neuronal loss in the entorhinal cortex of people with DS. The relatively low amyloid load (7 +/- 1%) and lack of correlation between the amyloid load and the volumetric or neuronal loss suggest that the contribution of beta-amyloid to neuronal loss in the entorhinal cortex is unsubstantial
— id: 32845, year: 1999, vol: 97, page: 156, stat: Journal Article,

Visual zone of the claustrum shows localizational and organizational differences among rat, guinea pig, rabbit and cat
Jakubowska-Sadowska, K; Morys, J; Sadowski, M; Kowianski, P; Karwacki, Z; Narkiewicz, O
1998 Jul;198(1):63-72, Anatomy & embryology
The retrograde axonal transport method was used to compare the topography and organization of the visual zone of the claustrum in rat, guinea pig, rabbit and cat. First, massive Fluoro-Gold injections were placed into the primary visual cortex and the secondary areas. Experiments showed differences in the location of the visual zone among the animals under study. In rat, the visual zone occupied the posteroventral part of the claustrum and spread to its anterior pole. In guinea pig, neurons projecting to the visual cortex were located dorsally in the posterior half of the claustrum. In rabbit, similarly to the rat, they were localized in the posteroventral part; however, they did not reach the anterior pole. In cat, neurons that project to the visual cortex were concentrated dorsally in the posterior fourth of the claustrum. In double-injection experiments, Fast Blue and Diamidino Yellow were placed into the primary and secondary visual areas in various combinations. The experiments showed that in the rat and the rabbit claustral neurons project to primary visual cortex (area 17) as well as to both secondary visual areas (areas 18a and b). Populations of neurons sending axons to the primary and secondary areas showed full overlap. The presence of double-labeled neurons indicates that some claustral neurons project both to the primary and secondary fields. In cat, neurons that project to the primary visual cortex appear to be clearly separated from those connected with the secondary visual area, as no double-labeled neurons were found. In all studied species, the double injections placed into the visual and primary somatosensory cortex did not result in any double-labeling neurons. Our results indicate that the location of the visual zone in the posterior part of the claustrum is a phylogenetically stable feature, whereas its dorsoventral shift as well as the extent toward the anterior pole is related to the particular species. The overlap of neurons projecting to the primary and secondary visual areas in the rat and rabbit as well as the separation of both projections in cat appear to reflect the higher degree of complexity of the visual system in the latter
— id: 67826, year: 1998, vol: 198, page: 63, stat: Journal Article,

N-methyl-D-aspartate receptor-mediated, calcium-induced calcium release in rat dentate gyrus/CA4 in vivo
Lazarewicz JW; Rybkowski W; Sadowski M; Ziembowicz A; Alaraj M; Wegiel J; Wisniewski HM
1998 Jan 1;51(1):76-84, Journal of neuroscience research
Previously, by using in vivo microdialysis, we demonstrated a huge release of 45Ca2+ from prelabeled tissues to dialysate that was evoked by application of N-methyl-D-aspartate (NMDA) to the rat dentate gyrus (DG) and sector 4 of the cornu ammonis. To establish the mechanism of this phenomenon, in the present study, we characterized its NMDA receptor dependence, investigated the mechanism of 45Ca2+ removal from the cells, and evaluated the possible involvement of calcium-binding protein calbindin D28k and of ryanodine receptors. Microdialysis experiments demonstrated a dose-response relation between NMDA and 45Ca2+ release and sensitivity of this phenomenon to inhibition by 10 microM MK-801 and 5 mM 5-(N,N-dimethyl)-amiloride, thus indicating the NMDA receptor dependence and a role of Na+/Ca2+ exchanger in mediating 45Ca2+ release from cells. Immunocytochemical experiments confirmed that DG granule cells in the investigated inbred rat strain are strongly calbindin D28k-immunopositive, indicating probable involvement of this protein. However, microdialysis studies demonstrated that NMDA-evoked 45Ca2+ release was suppressed by 100 microM dantrolene and 250 microM ryanodine, whereas 50 microM ryanodine stimulated this effect. This points to a key role in the investigated phenomenon of calcium-induced calcium release (CICR) via ryanodine receptors. To our knowledge, this is the first in vivo demonstration of NMDA-evoked CICR. We postulate the usefulness of microdialysis in such studies
— id: 32847, year: 1998, vol: 51, page: 76, stat: Journal Article,

Diffuse, lake-like amyloid-beta deposits in the parvopyramidal layer of the presubiculum in Alzheimer disease
Wisniewski HM; Sadowski M; Jakubowska-Sadowska K; Tarnawski M; Wegiel J
1998 Jul;57(7):674-683, Journal of neuropathology & experimental neurology
A characteristic feature of the parvopyramidal layer of the presubiculum of 6 individuals with Alzheimer disease (AD) was the presence of large, evenly distributed amyloid-beta (A beta) deposits, which in the end stage of the disease occupy 80.9 +/- 12.2% of the parvopyramidal layer. The strong reaction of A beta deposits with antibodies 4G8 (17-24 amino acids, aa), 6E10 (1-17 aa), and R165 (32-42 aa), and their weak reaction with antibody R162 (32-40 aa) indicate that potentially highly fibrillogenic A beta1-42 is a major constituent of presubicular amyloid. However, A beta deposits in the presubiculum are thioflavin-S- and Congo red-negative--and thus, nonfibrillar--even after 11 to 19 years of AD. The unique properties of presubicular amyloid appear to be related to their origin; amyloid-associated proteins such as apolipoproteins E, and AI, alpha1-antichymotrypsin, and heparan sulfate proteoglycan, which are promoters of fibrillization or stabilizers of A beta in neuritic plaques, are absent; activated astrocytes, which are the source of these proteins, are also absent. The unchanged number and distribution and the resting appearance of microglial cells revealed with RCA-I histochemistry suggest that they do not respond to diffuse A beta deposits. The source of nonfibrillar presubicular A beta is probably local neurons or neuronal projections to the parvocellular layer of the presubiculum. Neuronal, lake-like A beta deposition appears to be characteristic of AD pathology. The presubiculum is most likely the model brain structure for the study of amyloid of exclusively neuronal origin. The parvopyramidal layer of the presubiculum reveals only a small population of the neurons (2.5 +/- 2%) affected by neurofibrillary pathology
— id: 32846, year: 1998, vol: 57, page: 674, stat: Journal Article,

Rat's claustrum shows two main cortico-related zones
Sadowski, M; Morys, J; Jakubowska-Sadowska, K; Narkiewicz, O
1997 May 9;756(1-2):147-152, Brain research
Methods of retrograde axonal transport were employed to evaluate the topography and overlap of claustroneocortical connections in the rat. Fluorescent tracers Fast Blue (FB) and Diamidino Yellow (DY) were injected simultaneously in various combinations into the motor, somatosensory, auditory and visual cortical areas. Experiments showed that claustroneocortical projections are organized in two main cortico-related zones: sensorimotor and visuoauditory. The sensorimotor zone occupies the anterodorsal part whereas the visuoauditory occupies the posteroventral part of the claustrum. Between these two main zones only a scanty overlap was observed. In the sensorimotor zone a large overlap between neurons projecting to the motor and somatosensory cortical areas exists. The visuoauditory zone is characterized by a full overlap of neuronal populations projecting to the visual and auditory areas
— id: 67827, year: 1997, vol: 756, page: 147, stat: Journal Article,

Some claustral neurons projecting to various neocortical areas show morphological differences
Sadowski, M; Morys, J; Jakubowska-Sadowska, K; Narkiewicz, O
1997 ;56(2):65-76, Folia morphologica (Warsaw)
The morphology of claustral neurons projecting to the motor, somatosensory, auditory and visual cortical areas in the rat was analyzed by means of combination of axonal retrograde transport and morphometric analysis. Fluoro-Gold (FG) injections placed into various cortical fields resulted in labeling in the claustrum four neuronal types: pyramidal with thick main dendrite, oval with a few thin dendrites spreading out in various directions, fusiform possessing two main dendrites arising from opposite poles of the cell body and polygonal. Pyramidal neurons prevailed in populations of neurons projecting to the motor cortex of the contralateral hemisphere. Oval neurons outnumbered other types in populations projecting to the somatosensory, auditory and visual cortical fields. The number of fusiform and polygonal neurons did not exceed at 12.5% together in any populations. Neurons projecting to the contralateral hemisphere were the largest claustral neurons (mean cross-section are 167.19 +/- 2.9 micron 2) whereas neurons projecting to the motor cortex where the largest claustral neurons projecting ipsilaterally (141.89 +/- 2.22 micron 2). There was no significant difference between neurons projecting to the somatosensory (113.46 +/- 1.9 micron 2) cortex and to the visual (111.8 +/- 1.4 micron 2) cortex whereas neurons related to the auditory are (95.98 +/- 1.75 micron 2) were the smallest claustral neurons. These observations pointed out that the morphology of claustral neurons is closely related to a cortical area to which they send axons
— id: 67828, year: 1997, vol: 56, page: 65, stat: Journal Article,