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Vascular Mechanisms in Alzheimer Disease Pathogenesis

by
Peter M. Clifford
M.S., 2003
Rutgers University
Camden, NJ

Thesis Advisor: Robert G. Nagele, Ph.D.
Cell and Molecular Biology Program

Science Center, Room 290

Tuesday, April 8, 2008
12:00 pm


Abstract

Alzheimer`s Disease (AD) represents the most common neurodegenerative disorder, with 4.5 million Americans suffering its devastating effects. AD is marked by beta-amyloid (AB) peptide (AB42 predominantly) deposition within neurons and amyloid plaques in the brain parenchyma, along with neurofibrillary tangles. In addition, nearly all cases of AD demonstrate AB peptide deposition within the cerebral vasculature, known as cerebral amyloid angiopathy. Despite being the third most costly disease in the US, very little is known of the pathogenesis of AD, and there is no known treatment to slow or prevent neuronal attrition. Epidemiologic data suggests that the most consistent modifiable risk factors for developing AD are vasculopathies (eg. diabetes, hypercholesterolemia). These vascular disorders share the capacity to lesion the blood-brain barrier (BBB), a unique feature of the cerebrovasculature that normally prevents the efflux of plasma components into the brain parenchyma.
The goal of this investigation was to demonstrate the contribution of BBB compromise to AD pathogenesis through exposing brain parenchyma to plasma components, specifically, 1) AB42 peptides (synthesized largely by peripheral organs), and 2) anti-neuronal autoantibodies. Using pig (hypercholesterolemic/diabetic) and mouse (pertussis toxin) models of vascular injury, we provide evidence that lesioning of the BBB facilitates the efflux of plasma autoantibodies and AB peptides, allowing specific binding to their neuronal targets. AB42 is found to have a high affinity for a7nACh receptors, being expressed on the surface of both cholinergic neurons and vascular smooth muscle cells. We propose AB42 entry first requires binding to these receptors. Further, we provide both in vitro (mouse brain slice organotypic cultures) and in vivo (direct stereotaxic intracranial injection) evidence that anti-neuronal autoantibodies enhance the rate of AB42 internalization into neurons.
Finally, unique autoantibody profiles of demented and healthy individuals were determined via Western analysis. We have demonstrated that different individuals have both unique and common targets of anti-neuronal autoimmunity. Further, we have demonstrated that anti-neuronal autoimmunity extends across species, with all species tested demonstrating the ability to specifically recognize brain membrane proteins across species. Work performed here highlights the importance of maintaining the integrity of the BBB in the prevention of AD neurodegeneration.


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