Vincent T Marchesi MD, PhD
Anthony N. Brady Professor of Pathology and Professor of Cell Biology; Director, Boyer Center for Molecular Medicine
Research Interests
Pathogenesis of Alzheimer's disease; Neurodegeneration; Amyloid abeta metabolism, Auto-antibodies; Protein-folding
Current Projects
auto-antibodies to amyloid abeta peptidesneuro-protective antibodies
Research Summary
During the past decade my interest have focused on the
pathogenesis of Alzheimer's disease, one of the most destructive neurological
diseases that affects millions worldwide. This insidious disease becomes
clinically symptomatic during the sixth decade of life, but there are reasons
for believing that the disease process may begin one or two decades earlier,
and abnormal metabolism of amyloid abeta peptides may be an important
contributing factor.
I have been analyzing naturally occurring auto-antibodies
to the amyloid abeta protein as a measure of the body's response to either
elevated levels or abnormal forms of these peptides. It is my feeling that the
development of a reliable way to identify individuals who are risk for AD
before the disease is evident is a critical unmet need. This lack of early
detection hampers our ability to develop new therapies.
Extensive Research Description
Alzheimer’s dementia is the result of a cascade of
pathological processes that work
in concert over many decades to reduce the number of functioning neurons of the
human brain that are responsible
for memory and other executive actions. Neuronal cell death is believed
to be due to the accumulation of potentially toxic amyloid related peptides,
referred to as Abeta 40 and 42, through either their excessive production or
reduced clearance. Amyloid
deposits can be removed from animal and human brains by specific
antibody treatments, and clinical trials using this approach are now under way. Antibodies
to fragments of amyloid abeta peptides are now recognized as biological agents
with great therapeutic potential.
Two recent reports present evidence that naturally occurring
auto-antibodies to abeta might be neuro-protective. In one study
auto-antibodies to an aggregated form of abeta were found to be depressed in AD
patients, but, paradoxically, elevated in normal, young adults. A second report
describes a decrease in the incidence of AD in people treated with intravenous
immunoglobulin preparations Both results are consistent with the idea that
natural antibodies to abeta exist in all people and are depleted in advanced
AD.
Contrary
to these results, we have found that there is no clear correlation with levels
of anti-abeta antibodies and the clinical status of the donor. Antibodies to a
peptide fragment (p16-34) of abeta are elevated in many but not all individuals
with advanced AD. We have found that intravenous immunoglobulin preparations
also react with the p16-34 abeta fragment. If
naturally occurring antibodies to abeta are indeed neuro-protective, as the
available evidence suggests, it will be important to determine which epitopes
of abeta induce the protective response, and, equally important, to identify
the epitopes that might confer toxicity. The patho-physiological significance
of auto-antibodies to amyloid abeta peptides is clearly a complicated question
that deserves further study.
Selected Publications
- Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis. Matza D, Badou A, Jha MK, Willinger T, Antov A, Sanjabi S, Kobayashi KS, Marchesi VT, Flavell RA. Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9785-90.
- A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation. Matza D, Badou A, Kobayashi KS, Goldsmith-Pestana K, Masuda Y, Komuro A, McMahon-Pratt D, Marchesi VT, Flavell RA. Immunity. 2008 Jan;28(1):64-74.
- The relevance of research on red cell membranes to the understanding of complex human disease: a personal perspective. Marchesi VT. Annu Rev Pathol. 2008;3:1-9.
- An alternative interpretation of the amyloid Abeta hypothesis with regard to the pathogenesis of Alzheimer's disease. Marchesi VT. Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9093-8.
