Scientists in NYU Langone’s Department of Psychiatry conduct translational research on Alzheimer’s disease (AD) and related dementias in the Center for Dementia Research (CDR) at The Nathan S. Kline Institute for Psychiatric Research. The CDR, led by Ralph A. Nixon, MD, PhD, comprises a faculty of 9 principal investigators and a staff of more than 50 conducting studies on etiology, prevention, and treatment of degenerative disease.

Recognized for an innovative conceptual approach to AD therapy development, CDR researchers received more than $30 million in National Institutes of Health (NIH) grants during the last 3 years, including a fourth renewal of a $12 million multi-investigator NIH Program Project Grant to continue pioneering investigations on anomalies of the endosomal–lysosomal pathway that arise in the AD brain before β-amyloid deposition and decades before clinical AD symptoms. These studies have identified novel disease targets and yielded candidate therapeutic agents, including one recently shown to lower cerebrospinal fluid (CSF) markers of neurodegeneration in a phase 2 clinical trial, and additional patented compounds being validated in the CDR or with industry partners.

Center programs in the past 10 years have yielded more than 300 peer-reviewed publications, which have been cited more than 60,000 times, contributing to NKI’s ranking in the top 1 percent of research institutions nationwide in citations per publication.

Research accomplishments by CDR investigators include discovery of the first amyloid precursor protein (APP) mutation in a human disease and the earliest known disease-specific neuronal defects in the AD brain. Additional CDR discoveries include novel mechanisms linking genes causing early onset AD to defects in cellular waste clearance (autophagy) that are the basis of new drug discovery programs worldwide. The paradigm-shifting discovery of novel synaptic roles for neurofilament proteins implicated prominently in neuropsychiatric diseases has revealed new clues to pathogenesis and a basis for the emerging clinical utility of these proteins as disease biomarkers.

Synapse Dysfunction in Alzheimer’s Disease and Other Dementias

Dementias are well recognized to originate from dysfunction of synapses. Collaborating scientists in the Laboratories for Molecular Neuroscience, led by Dr. Ralph A. Nixon, address the multifactorial basis for progressive synaptic failure in AD.

The Nixon lab has shown that endosomal–lysosomal defects, the earliest neuronal abnormalities arising in AD, stem directly from the proteins encoded by genes that cause the disease (amyloid precursor protein and presenilins) or that increase AD risk. We established that abnormal signaling by endosomes disrupts synaptic dysfunction and survival of cholinergic neurons leading to memory decline. Novel mice modeling the endosomal missignaling seen in AD recapitulate the key prodromal and degenerative features of AD. A recent phase 2 clinical trial of neflamapimod/VX-7645, a small molecule inhibitor of abnormal endosome signaling, is one of the first agents to significantly slow CSF marker evidence of neurodegeneration in AD subjects.

Related lysosomal dysfunction causes the hallmark neuritic dystrophy of AD and the uniquely massive accumulations of metabolic waste seen in AD neurons, including the build-up of neurotoxic amyloid and tau, and which ultimately results in extensive neuron loss. We are defining the two-way trafficking of molecules and organelles between the nucleus and the synapse critical to maintaining diverse synaptic functions related to cognition. An accelerated program is ongoing to validate preclinically new molecular targets identified in our research using newly developed methods to quantify in vivo the therapeutic efficacy of new drug strategies against these targets.

Another major research effort in the Nixon lab focuses on the axonal transport, assembly, and turnover of cytoskeletal proteins and their dysregulation within synapses in relation to dementing diseases. Current multiomic and functional analyses of synapses are tracking the interactions of neurofilament subunits with synaptic proteins genetically linked to multiple neurocognitive disorders.

Other principal investigators in the Laboratories for Molecular Neuroscience, including Dun-Sheng Yang MD, PhD, Mala V. Rao, PhD, and Aidong Yuan, MD, are addressing additional facets of synaptic failure.

Restoring Defective Waste Recycling in the Brain as a New Therapy for Alzheimer’s Disease

Dr. Yang studies AD pathogenesis in the human brain and in mice at the molecular, cellular, and system levels. The Yang Lab focuses on how neurons degrade and recycle cell constituents via lysosomes—the process termed autophagy (self-eating). Additionally, they investigate the molecular basis for early and progressive corruption of this pathway in AD, which leads to build-up of neurotoxic proteins and ultimately neuronal death. Dr. Yang and his colleagues use AD models and novel transgenic in vivo reporters to evaluate lysosomal failure in the intact brain, which allow his team to validate innovative therapeutic approaches to remediate early failure of the autophagic–lysosomal system in AD.

Neurodegenerative Mechanisms in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis

Dr. Rao and colleagues in the Rao Lab, address molecular mechanisms of neuron cell death in AD and amyotrophic lateral sclerosis (ALS), focusing on multiple proteolytic systems in neurons that serve as initiators and executioners of cell death programs relevant to brain disease. A particular interest is the calpain protease system activated in various neurological conditions and an important disease target. Our investigations of calpastatin, a highly specific natural inhibitor of calpains, as a proof-of-principal therapy have demonstrated striking alleviation of disease symptoms and life extension in models of AD, tauopathy, Huntington disease, Parkinson’s disease, and ALS, which has strongly encouraged the global search for specific small-molecule calpain inhibitors. Investigations on calpains and autophagy in relation to axonal transport and metabolism of cytoskeletal proteins, especially neurofilament proteins, have uncovered key mechanisms regulating axonal and synaptic function in the healthy brain and defined consequences for motor and cognitive function of these disease-related proteolytic disruptions.

Novel Roles of Protein Networks in Synapses That May Underlie Dementia

The longstanding focus on neurofilament biology by Dr. Yuan and colleagues in the Yuan Lab recently revealed novel roles for each of the four component subunits in regulating synaptic plasticity and specific neurotransmitter receptors (NMDA, D1). Ongoing proteomic and genomic analyses of isolated synapses have identified distinctive networks enriched in the proteins implicated in multiple cognitive disorders, including AD, frontotemporal dementias, and certain neurodevelopmental disorders.

In addition to modulating neurotransmission, individual neurofilament subunits integrated within specific synaptic networks are suspected to control local protein synthesis and endocytosis—synaptic processes known to fail early in dementia development. Molecular interrelationships among proteins composing specific subnetworks are being investigated in unique genetic models to clarify roles in endocytosis regulation, synaptic plasticity, and cognition in the context of AD and other dementias.

Altered Excitability and the Etiology of Diverse Psychiatric Conditions

Research led by Helen E. Scharfman, PhD, in the Scharfman Lab, focuses on altered excitability and the etiology of diverse neurological and psychiatric conditions. Our scientists mainly use animal models, assessing rodents with seizures or with a mutation leading to AD brain pathology and cognitive impairments. Our goals are to use drugs to normalize this excitability in rodents and determine which agents improve symptoms. Our intent is to develop new therapeutic approaches for humans.

We are defining the fundamental circuitry of complex brain areas like the hilus of the dentate gyrus; as such, one of our projects addresses the normal role of neurons born in the dentate gyrus during adulthood. Adult-born neurons may keep the neural activity of the dentate gyrus low, which could be crucial to dentate gyrus cognitive functions. We are also studying the mossy cells of the dentate gyrus, in addition to hippocampal area CA2 and whether it is more powerful than its size would predict.

Our translational research assesses the use of selective suppression or enhancement of adult-born neurons to treat epilepsy and whether inhibiting mossy cells or CA2 can influence epilepsy in animal models. Our lab also investigates early abnormal electrical activity as a biomarker in an AD mouse model and therapeutic approaches to suppressing this activity.

Changes in Vesicular Trafficking in Alzheimer’s Disease Neurons

Research in the Levy Lab, led by Efrat Levy, PhD, aims to understand the pathogenic processes that lead to AD and related neurodegenerative disease. In recent years, our focus has been on changes in vesicular trafficking in neurons during the disease, including what are now foundational studies of the role of extracellular vesicles as either protective or pathogenic vehicles within the brain. Our findings suggest that the secretion of extracellular vesicles is a mechanism for the clearance of accumulated material when disease-mediated dysfunctions prevent the efficient transport of cargo for degradation inside the cell. Ongoing studies are investigating the effects of neuronal abnormalities on extracellular vesicles secretion and the utilization of extracellular vesicles as protective vehicles. Extracellular vesicles transport their content for long distances through the extracellular space and into recipient cells and can deliver protective proteins and other molecules, providing a novel therapeutic approach for AD.

We are currently studying the brain of AD patients and mouse models to determine the role of the generation and secretion of extracellular vesicles in either protection or pathogenicity in the disease. In one project, we are investigating the enhanced release of extracellular vesicles as a potential therapy, preventing neuronal loss in the brain due to accumulation of toxic material.

We are also studying the apolipoprotein E (APOE) genotype, an important determinant of an individual’s risk for developing AD. While the APOE2 allele appears to be protective, APOE4 increases the risk for the disease as compared with carriers of the neutral-risk APOE3 allele. Additionally, APOE4 expression can lead to cognitive decline during aging that is independent of characteristic AD pathology.

Our data show neuronal abnormality in the brain of APOE4 carriers and lower levels of extracellular vesicles released into the brain extracellular space. Compromised vesicle production is likely to have adverse effects, diminishing a cell’s ability to eliminate accumulated toxic material, leading to neuron vulnerability in APOE4-expressing individuals. Extracellular vesicular dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of APOE4 expression, contributing to higher risk of developing AD. We are currently investigating the changes in the brain of carriers of APOE4 allele as compared with the APOE2 allele to identify therapeutic targets based on the differences in release and content of extracellular vesicles due to the different APOE genotypes. Our translational research also involves the delivery of proteins and peptides that prevent the development of AD via extracellular vesicles.

Cognitive Symptoms in Alzheimer’s Disease and Their Treatment

The Ohno Lab, led by Masuo Ohno, PhD, studies the mechanisms of AD, specifically β-secretase 1 (BACE1), which initiates the production of harmful β-amyloid (Aβ) peptides, the major constituent of amyloid plaques. Our researchers also aim to develop disease-modifying therapy to prevent or treat memory deficits.

By applying gene knockout and small-molecule inhibitors to mouse models, we are finding that successful therapeutic BACE1 inhibition for cognitive benefit needs to start during early or asymptomatic disease stages. We are also investigating BACE1-elevating mechanisms, which can represent novel therapeutic targets. Our goal is to increase BACE1-inhibition efficacy in ameliorating memory deficits, while avoiding untoward effects.

The Vulnerability of Neuronal Cell Types to Brain Disease

The Ginsberg Lab, led by Stephen D. Ginsberg, PhD, aims to understand mechanisms underlying selective vulnerability associated with AD. Our researchers extensively characterize individual populations of neurons from AD and Down syndrome models and postmortem brains using high-throughput gene assays. Individuals with Down syndrome develop neuropathological changes seen in early AD.

We are currently profiling selectively vulnerable neurons and comparing them with relatively spared neurons during AD onset and progression. We are also analyzing selective vulnerability in the hippocampus by evaluating several different hippocampal neuron subtypes simultaneously. Animal studies suggest that specific gene pathways associated with neuron survival and intracellular trafficking are important for normal neuron function, partially explaining why some neurons are vulnerable and others resilient. Parallel studies in the postmortem brain indicate that individual genes and their encoded proteins in these critical pathways are disrupted in AD, especially within vulnerable neurons early in the disease.

Our translational research is directed toward reversing the dysregulation of genetic pathways in vulnerable neurons. One project employs a chronic dietary restriction approach in adult AD mice. Another uses an early development dietary supplementation in Down syndrome mice to positively affect vulnerable hippocampal neurons as adults. We then evaluate treatment benefits using the single-population profiling procedure for potential therapeutic development.

Neurodegeneration as a Consequence of Disrupted Neuronal Endosomal Pathway Function

The Mathews Lab, led by Paul M. Mathews, PhD, focuses on vulnerable cellular trafficking pathways where altered function can lead to AD and neurodegenerative disorders. Our researchers primarily study the interrelationship between AD pathology and dysfunction of the neuronal endosomal pathway. The primary objective of our research is to identify how changes in neuronal endosomal function contribute to pathogenic changes that lead to AD and related neurodegenerative disorders.

We are currently examining the impact that multiple risk factors for AD (e.g., expression of the APOE4 allele, dietary cholesterol, and diabetes) have on endosomal pathway changes that contribute to the likelihood of neurodegeneration during aging. Additionally, we are examining the role that the β-cleaved C-terminal fragment of the amyloid precursor protein (βCTF of APP) plays in regulating the endosome-to-Golgi recycling pathway mediated by the retromer complex, an endosomal trafficking route that is dysfunctional in both AD and Down syndrome.

We have identified neuronal endosomal alterations linked to the expression of APOE4, as well as beneficial effects of the APOE2 allele. Additionally, APOE4 expression appears to alter membrane lipid composition in the endosomal pathway. Based on this prior research, we are using genetic manipulations, small-molecule pharmaceuticals, and biologicals to rescue neuronal endosomal function in AD-related models using both in vitro and in vivo system.

Current Grants

Our research is supported by foundation and National Institutes of Health grants.

CHDI Foundation

In Vivo Evaluation and Therapeutic Modulation of Neuronal Autophagy Flux in HD Mouse Models

National Institute on Aging

Cell and Molecular Pathobiology of Alzheimer’s Disease; 5P01AG017617-18

Endosome Dysfunction in Alzheimer’s Disease: Mechanisms and Role in Pathogenesis; R01AG062376-02

Hyperexcitability in Alzheimer’s Disease; 5R01AG055328-03

Postdoctoral Research Training in Neurodegenerative Disorders and the Aging Brain; 5T32AG052909-03

Preventing Early Events in a Beta-Driven Pathology In Vivo; 5R01AG056732-03

Neuronal Protective Apolipoprotein E2–Mediated Endocytic and Exocytic Pathways; 1RF1AG057517-01

Brain Exosomes Mediate Cocaine-Induced Addiction; 5R01DA044489-03

National Institute of Neurological Disorders and Stroke

Diverse Roles of Adult Dentate Gyrus Neurogenesis; 5R01NS081203-05

The Role of CA2 in Epilepsy and Social Comorbidity; 1R01NS106983-01

Accelerated Depletion of Hippocampal Neural Stem Cells in Neurological Disease; 5R01NS086965-05

National Institute of Mental Health

Hilar Mossy Cells and Dentate Gyrus Function; 5R01MH109305-04

Research Training

We provide a range of training opportunities in basic and translational neuroscience, psychiatric research, and cross-disciplinary collaborative research. We have an exceptional track record of preparing trainees for independent faculty and leadership positions in academia, industry, and scientific foundations. Graduate students, postdoctoral fellows, and recent college graduates with diverse interests are welcome in many of our labs.

Research Faculty

Our research faculty are leaders in the field of dementia research.

Ralph A. Nixon, MD, PhD
Stephen D. Ginsberg, PhD
Efrat Levy, PhD
Paul M. Mathews, PhD
Masuo Ohno, PhD
Mala V. Rao, PhD
Helen E. Scharfman, PhD
Dun-Sheng Yang MD, PhD
Aidong Yuan, MD

Contact Us

For more information about the Department of Psychiatry’s work through the Center for Dementia Research at Nathan Kline Institute, please contact Dr. Nixon at ralph.nixon@nyulangone.org.

Featured Publications

Our faculty who conduct research through the center frequently publish in peer-reviewed journals. Here is a selection of our most recent publications.