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Implications of blood-brain barrier breakdown on Alzheimer`s disease pathogenesis

by
Eli Levin
Bachelor of Science, 2005
The College of New Jersey

Thesis Advisor: Robert Nagele, Ph.D.

Cell and Molecular Biology Program

Science Center, Room 290

Thursday, April 29, 2010
12 pm


Abstract

Alzheimer`s disease (AD), the most common neurodegenerative disorder, is characterized by progressive memory loss, cognitive decline, behavioral changes, and eventual death. Pathological hallmarks include neurofibrillary tangles, amyloid deposits in cells and plaques, inflammation, synaptic loss, dendrite retraction, and neuronal degeneration. In addition, virtually every AD brain demonstrates blood-brain barrier (BBB) breakdown. Although the BBB is known to tightly regulate the passage of serum components into the brain, the causes and effects of its disruption in AD remain largely unclear.

The purpose of this investigation was to determine the implications of BBB breakdown on AD pathogenesis. To explore effects of predisposing factors for AD on the BBB and the brain parenchyma, we utilized a diabetic, hypercholesterolemic (DHC) porcine model. This model provides evidence that diabetes and hypercholesterolemia are capable of inducing AD-like pathology. DHC porcine brains possess extensive lesions of the BBB concurrent with efflux of plasma components, including antibodies and amyloid. Moreover, our DHC model is found to form intraneuronal deposits of extravasated amyloid.

Antibodies are a sera component commonly found to efflux and bind to neurons in the brains of AD patients and animal models of AD. To determine the prevalence of these brain-reactive autoantibodies in humans, we analyzed sera from individuals with AD and other neurodegenerative diseases as well as controls. Western analysis revealed the nearly ubiquitous presence of brain-reactive autoantibodies in sera regardless of disease state. However, these antibodies would only gain access to targets in the brain parenchyma under conditions of BBB compromise.

Finally, we sought to elucidate the response of neurons in the brain to damage caused by evolving AD pathology, including the efflux of brain-reactive autoantibodies and amyloid. Through single- and double-label immunohistochemistry, we provide evidence that there is a neuronal damage-response mechanism to combat synaptic loss and dendrite retraction. Vimentin, a protein required for embryonic neurite extension, is expressed by damaged neurons in AD brains, as well as those subjected to mechanical injury. Findings detailed here provide strong evidence of the importance of maintaining or reestablishing BBB integrity to prevent or limit pathology associated with AD and other neurodegenerative diseases.


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