Nixon Lab

Synapse Dysfunction in Alzheimer’s Disease and Other Dementias

Dementias are well recognized to originate from dysfunction of synapses. Collaborating scientists in the Center for Dementia Research, led by Dr. Ralph 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 misssignaling 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 multi-omic 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, as well as Research Project Manager Ju-Hyun Lee, PhD, are addressing additional facets of synaptic failure.

Laboratories for Molecular Neuroscience

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

Dr. Dun-Sheng 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. Mala 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. David 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.

Autophagy-lysosome Pathway in Neurodegenerative Disease, Including Alzheimer’s Disease

Dr. Ju-Hyun Lee has been extensively involved in analyses of Autophagy and the pathology of endosomal-lysosomal system changes in relation to neurodegeneration using both in vitro and in vivo in Alzheimer’s disease (AD) models, and postmortem AD human brain. The Lee Lab conducts studies at the cellular level to identify the early lysosomal acidification (pH) changes in neurons that lead to the onset and progression of AD and identified changes in one of the surveillance systems inside neurons, known as autophagy, that underlie the functional alterations in the brain of AD patients. Moreover, research in his lab is providing fundamental insights into the regulation of Autophagy-lysosome pathway (ALP) in vivo in neurons and holds exceptional promise for understanding how ALP dysfunction propels amyloid pathology in Alzheimer’s disease. The further potential for accelerating translational studies of ALP modulators as therapeutic agents in neurological disorders fulfills an additional, urgent, need in the ALP alteration-mediated neurodegeneration field.

Selected Publications

Lie PPY, Lang Y, Goulbourne CN, Berg MJ, Stavrides P, Huo C, Lee J-H, Nixon RA. Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function. Sci Adv. 2022.vol 8(17)doi: 10.1126/sciadv.abj5716 Click for abstract

Lie PPY, Yang DS, Stavrides P, Goulbourne CN, Zheng P, Mohan PS, Cataldo AM, Nixon RA. Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons. Cell Rep. 2021 Apr 27;35(4):109034. doi: 10.1016/j.celrep.2021.109034. PubMed PMID:33910020
Click for abstract

Pensalfini A, Kim S, Subbanna S, Bleiwas C, Goulbourne CN, Stavrides PH, Jiang Y, Lee J-H, Darji S, Pawlik M, Huo C, Peddy J, Berg MJ, Smiley JF, Basavarajappa BS, Nixon RA. Endosomal Dysfunction induced by directly overactivating Rab5 recapitulates prodromal and neurodegenerative features of Alzheimer’s disease. Cell Rep 2020 Nov24:33(8):108420 PMID: 33238112
Click for abstract

Publications

All publications

Nixon Lab Members

Chris Goulbourne, PhD Director of Electron Microscopy 845-398-2192 Chris.Goulbourne@NKI.rfmh.org	Mala Rao, PhD Principal Investigator 845-398-5547 Mala.Rao@NKI.rfmh.org	Dun-Sheng Yang, MD, PhD Principal Investigator 845-398-5436 Dun-Sheng.Yang@nki.rfmh.org	David Yuan, MD, PhD Principal Investigator 845-398-5438 David.Yuan@NKI.rfmh.org
Martin Berg Research Scientist 845-398-3433 Martin.Berg@NKI.rfmh.org	Cynthia Bleiwas Research Scientist 845-398-5528 Cynthia.Bleiwas@NKI.rfmh.org	SandipKumar Darji Research Scientist 845-398-5436 Sandipkumar.Darji@NKI.rfmh.org	Eunju Im, PhD Postdoctoral Researcher 845-398-5438 Eunju.Im@NKI.rfmh.org
Ying Jiang, PhD Research Scientist 845-398-5465 Ying.Jiang@NKI.rfmh.org	Ju-Hyun Lee, PhD Research Project Manager 845-398-5438 Ju-Hyun.Lee@NKI.rfmh.org	Sandeep Malampati, PhD Postdoctoral Researcher 845-398-5455 Sandeep.Malampati@NKI.rfmh.org	James Peddy Research Assistant 845-398-5436 James.Peddy@NKI.rfmh.org
Kuldeep Sachdeva, PhD Postdoctoral Researcher 845-398-5455 Kuldeep.Kuldeep@NKI.rfmh.org	Philip Stavrides Research Scientist 845-398-5436 Philip.Stavrides@NKI.rfmh.org	Lang Yoo, PhD Postdoctoral Researcher 845-398-5438 Lang.Yoo@NKI.rfmh.org