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 miss-signaling 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, are addressing additional facets of synaptic failure. 

Publications

All publications

Nixon Lab Members

 

Marty Berg Research Scientist	Jiang Ying Research Scientist	Ju Hyun Lee Research Project Manager	Mohan Panaiyur Research Scientist	Dun-Sheng Yang Research Scientist	David Yuan Project Manager
Pearl Lie Postdoctoral Fellow	Eunju Im Postdoctoral Fellow	Anna Pensalfini Postdoctoral Fellow	Philip Stavrides Research Scientist	Sandip Darji Research Scientist	Lang Yoo Postdoctoral Fellow
Chris Goulbourne EM Director	Cynthia Bleiwas Research Assistant IV	James Peddy Research Technician	Lauren Whyte Postdoctoral Fellow	Sandeep Malampati Postdoctoral Fellow