Vincent T Marchesi MD, PhD
Anthony N. Brady Professor of Pathology and Professor of Cell Biology; Director, Boyer Center for Molecular Medicine
Pathogenesis of Alzheimer's disease; Neurodegeneration; Amyloid abeta metabolism; Auto-antibodies; Protein-folding
Current Projectsauto-antibodies to amyloid abeta peptides
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
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.