Date Approved

8-2016

Document Type

Dissertation

Degree Name

PhD in Cell & Molecular Biology

Department

Cell Biology

College

Graduate School of Biomedical Sciences

First Advisor

Robert Nagele, PhD

Committee Member 1

Ronald Ellis, PhD

Committee Member 2

Paola Leone, PhD

Committee Member 3

Venkataswar Venkataraman, PhD

Committee Member 4

Donald A. Barone, DO

Subject(s)

Blood-Brain Barrier, Dementia, Alzheimer Disease, Autoantibodies, Neurodegenerative Diseases, Plaque, Amyloid

Disciplines

Cell Biology | Laboratory and Basic Science Research | Medicine and Health Sciences | Molecular and Cellular Neuroscience | Molecular Biology | Nervous System Diseases | Pathological Conditions, Signs and Symptoms | Translational Medical Research

Abstract

Brain homeostasis can be affected in a number of ways that lead to gross anatomical, cellular, and molecular disturbances giving rise to diseases like Alzheimer’s disease (AD) and related dementias. Unfortunately, the mechanistic pathoetiology of AD’s hallmark features of cerebral amyloid plaque buildup and neuronal death are still disputed. Using human brain AD sections, immunohistochemistry experiments revealed internalized surface proteins, co-localized to an expanded lysosomal compartment. Other stains for amyloid-β1-42 (Aβ42) and various immunoglobulin (Ig) species displayed them leaking out of the cerebrovasculature through a dysfunctional blood-brain barrier (BBB), binding to neurons in the vicinity, and localizing to intracellular vesicles presumably en route to lysosomal degradation. To more clearly elucidate this process, a cell culture model system was established and assayed for aspects of an autoantibody (aAb)-mediated enhancement of amyloid internalization.

In a pilot study investigating the role of inhaled anesthetics on the BBB as an acute irritant, we were able to demonstrate the leakage of IgG into the cerebral cortex. As in our AD models and pathological slides, the aAbs bound to subsets of neurons and were increased in regions of BBB breakdown. The extent was directly proportional to the age of the animal, which parallels the incidence of post-operative delirium seen in the clinical setting, thus suggesting a potential link.

Lastly, the ability to assay BBB integrity clinically has remained elusive, yet is invaluable for pre-symptomatic diagnoses and potential treatments. In a previously published study using a diabetic young pig model, pathological changes were demonstrated in the brain parenchyma that faithfully recapitulated AD-type changes. The retinas of these pigs were also investigated for regions of blood-retinal barrier (BRB) leakage and neuronal pathology in the ganglion cell layer. This allows for a juxtaposed comparison between the BBB and the BRB, and opens up doors to use the BRB clinically as a surrogate system to detect ongoing BBB pathology. Taken together, these studies broaden the landscape of knowledge surrounding AD and other neurological diseases, providing new perspectives on pathogenesis, diagnosis, and treatment efforts.

Download

Share

COinS