Correcting the Loss of Brain Connectivity in Alzheimer's Disease

Seth S Margolis, PhD
Johns Hopkins University School of Medicine (Baltimore, MD, United States)
Year Awarded:
Grant Duration:
July 1, 2012 to June 30, 2014
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern
Seth S Margolis, PhD

Correcting Synapse Loss in the Alzheimer's Disease Brain


Several recent studies, including those of Dr. Seth Shatkin Margolis and colleagues, suggest the intriguing hypothesis that neurodegenerative disorders such as Alzheimer's disease (AD) share a common causative feature, which is the loss of appropriate functional connections in the brain. Dr. Margolis's team has identified a natural inhibitor of brain development and nerve cell connections that is increased in the AD brain. This project is aimed at discovering which symptoms of AD are due to the increased amount of this inhibitor and identifying small molecule blockers to this inhibitor as potential new treatments for AD.


Dr. Seth Shatkin Margolis and colleagues aim to correct the loss of brain connectivity in Alzheimer's disease by blocking a natural inhibitor of brain development that is abnormally increased in the AD brain.

These researchers will use genetic approaches in AD mice to reduce the levels of a major natural inhibitor of brain development, called Ephexin5. Using these mice, they will look for those AD deficits that revert back to an unaffected state following the reduction of Ephexin5. Also, the team will use a two-pronged approach to screen for small molecule drugs that block Ephexin5 activity and improve brain functions in the living animal.

Alzheimer's disease is a complex disorder that results from an assortment of causative factors, including genetic mutations, environmental influence, aging, loss of brain cell connections, brain-cell death, the presence of neurofibrillary tangles, and plaque formation. Despite the likelihood that each of the AD causative factors is interrelated, Margolis and colleagues believe that a single treatment to alleviate all symptoms and deficits in AD is not plausible. They believe treating AD requires a cocktail of therapies, each aimed at different underlying causative factors of AD. Thus, the focus of their attention is toward an unexplored area of AD research that provides increasing evidence for AD phenotypes resulting from loss of connectivity in the brain.

If successful, the team will be among the first to determine to what capacity AD symptoms are corrected upon blocking the actions of an abnormally expressed natural inhibitor of brain development. In addition, their approach will provide a platform for future collaborative studies aimed at developing blockers of other newly identified inhibitors of brain development in AD.  They hope their research will aid in the ongoing pursuit of diminishing the impact Alzheimer's disease has on individuals, families, and the human condition.

About the Researcher

Dr. Margolis received his Bachelor of Science in Biochemistry at the University of Rochester in Rochester, NY. He completed his doctoral studies in the laboratory of Dr. Sally Kornbluth at Duke University Medical Center in Durham, North Carolina in the department of Pharmacology and Cancer Biology. In 2006, Margolis joined the laboratory of Dr. Michael Greenberg in the department of Neurobiology at Harvard University in Boston, Massachusetts as a postdoctoral fellow. During his postdoctoral tenure he focused his efforts on the molecular pathways that regulate excitatory synapse formation and investigated their relevance to the pathophysiology of cognitive disorders. In September of 2011, Margolis joined the Johns Hopkins University School of Medicine in Baltimore, Maryland as an Assistant Professor in the Department of Biological Chemistry. Currently, Margolis' research group is investigating the role of key negative regulators of synapse formation, which contribute to the pathophysiology of synapse loss in the Alzheimer's disease brain.


Sell GL, Schaffer TB, Margolis SS. Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice. J Clin Invest. 2017 Mar 27. pii: 85504. doi: 10.1172/JCI85504. [Epub ahead of print] PubMed PMID: 28346227. PubMed Icon Google Scholar Icon

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