Vincent T. Marchesi, M.D., Ph.D.

Anthony N. Brady Professor of Pathology and Cell Biology Director, Boyer Center for Molecular Medicine
Marchesi lab website Phone: (203) 737-2775 / -2263 e-mail: vincent.marchesi@Yale.edu		Department of Pathology Yale University School of Medicine 295 Congress Ave P.O. Box 208023 New Haven, CT 06520-8023 <Courier Address> 295 Congress Avenue, BCMM 109 New Haven, CT 06519-1418

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Research Interests: Pathogenesis of Alzheimer's disease and mechanisms of neurodegeneration.

I am studying the role of oxidative stress in the pathogenesis of Alzheimer's disease. A special class of APP mutations has been described in families with early onset AD which are scattered throughout the world and named after the sites of the founder families. These include Dutch, Iowa, and Arctic mutations (D/I/A), as well as others, and they generate abeta peptides with unusual properties. These peptides are more fibrillogenic than regular abeta and they are relatively resistant to proteolytic digestion by neprilysin and IDE. Patients who have these mutations have extensive deposits of abeta peptides around their blood vessels, a condition known as cerebral amyloid angiopathy (CAA), which predisposes them to cerebral micro-hemorrhages in addition to the amyloid plaques seen in patients with sporadic AD. Since reactive oxygen species (ROS) are known to oxidize guanine bases in both DNA and RNA, and oxidized APP mRNA could create translation errors, we are exploring the possibility that somatic mutants of the above described genetic variants may be produced in the brain as a result of oxidative stress. These peptides might  be both vasculotropic and resistant to degradation, and over time they could lead to CAA and the Alzheimer's syndrome.

Selected publications

Vincent T. Marchesi
An alternative interpretation of the amyloid A{beta} hypothesis with regard to the pathogenesis of Alzheimer's disease
PNAS 2005 102: 9093-9098

          
Akihiko Komuro, Yutaka Masuda, Koichi Kobayashi, Roger Babbitt, Murat Gunel, Richard A. Flavell, and Vincent T. Marchesi
The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells
PNAS 2004 101: 4053-4058