Abstract

Alzheimer’s disease (AD) is the most common form of dementia and completely lacks any viable, long-term therapeutic intervention. This is partly due to an incomplete understanding of AD etiology and the possible confounding factors associated with its genotypic and phenotypic heterogeneity. Cerebral amyloid angiopathy (CAA) is a common, yet frequently overlooked, pathology associated with AD. A pathological hallmark of AD consists of extracellular amyloid-beta (Aβ) deposits, while CAA

manifests with deposition Aβ within the smooth muscle layer of cerebral arteries and arterioles. The role of Aβ in AD and CAA pathophysiology has long been controversial. Although it may have toxic effects at super-physiological levels, Aβ load does not necessarily correlate with cognitive demise in humans. Described in this dissertation is an alternative viewpoint that the toxicity afforded by Aβ could be due, in part, to complement system activation—a potent inflammatory cascade, which left unchecked can cause robust cell death. We have found increased levels of the lytic Membrane Attack Complex (MAC) on vessels harboring CAA compared to vessels from AD patients without CAA and pathological controls. Additionally, the same vessels also show trending decreases in the endogenous MAC inhibitor, CD59. We believe the differential complement phenotype on vessels could be due to an upstream shift in how

Aβ is trafficked to the blood stream for clearance. We found more Aβ bound to the microglial CD11b receptor through complement C3b in CAA patients compared to AD and control subjects. Additionally, 75% of CAA patients in this cohort harbor the CAA risk haplotype rs6656401 at the CR1 gene, which seems to modify the localization of CR1 molecules from the membrane to endosomal structures. Because CR1 functions on the cell surface to block C3b generation, mislocalization to intracellular compartments

may explain the increased C3b found in subjects with CAA. Increased availability of parenchymal C3b to bind Aβ may explain the robust staining of MAC on CAA blood vessels. These observations in human postmortem brain help explain the high frequency of microbleeds and hemorrhage associated with CAA and may offer a novel therapeutic target to reduce these life-threatening events.

LLU Discipline

Anatomy

Department

Basic Sciences

School

School of Medicine

First Advisor

Kirsch, Wolff M.

Second Advisor

Kirby, Michael

Third Advisor

Pearce, William J.

Fourth Advisor

Soriano, Salvador

Fifth Advisor

Vinters, Harry V.

Sixth Advisor

Wall, Nathan

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2013

Date (Title Page)

6-1-2013

Language

English

Library of Congress/MESH Subject Headings

Alzheimer's Disease Pathology; Dementia; Brain - pathology; Cerebral Amyloid Angiopathy - pathology; Biological Markers; Hemorrhage; Intracerebral Hemorrhage; Neuroglia; Cerebrovascular Disease

Subject - Local

Cerebral Amyloid Angiopathy, Microglia, Brain microbleeds

Type

Dissertation

Page Count

138 p.

Digital Format

Application/PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses & Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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