Abstract

Alterations in brain metals homeostasis and particularly brain iron overload have been postulated to play a role in Alzheimer's disease, contributing to oxidative stress and neuronal injury; however, the source of this iron is not clear and may be due to metabolic derangement(s), failed iron clearance mechanisms or exogenous deposition such as through bleeding. This series of studies was designed to evaluate the extent of metals dyshomeostasis in the Alzheimer's disease brain and specifically whether microvascular bleeding is a major contributor to Alzheimer's disease-related iron overload. Cerebral amyloid angiopathy (CAA) is a vascular manifestation of Alzheimer's disease present to some degree in up to 95% of Alzheimer's disease patients. This vasculopathy results in vascular inflammation and fragility which produces clinically detectable bleeding (by susceptibility weighted MR imaging) in many Alzheimer's disease patients. We analyzed brain iron levels by gold-standard atomic absorption spectrometry in brain tissue from patients with severe CAA, in those with Alzheimer's disease without significant vascular involvement and in aged control tissue. We also observed iron, zinc and copper in these tissues histologically by novel techniques to qualitatively assess their association with vascular and perivascular abnormalities. Increased iron in the subset of Alzheimer's disease patients with CAA is accompanied by increased levels of heme degradation enzymes, heme oxygenase and biliverdin reductase. Finally, because the mechanism(s) underlying vascular fragility in CAA is unknown, we evaluated the role of terminal complement on cerebrovascular elements in the setting of CAA. This may provide mechanistic clues to how the structural stability of arterioles is undermined in this microangiopathy. If iron overload is a feature of CAA rather than a more general feature of Alzheimer's disease, it is possible that chelation therapies will be more effective for the subset of Alzheimer's patients with severe vasculopathy. This information combined with an effective clinical test for CAA has the potential to refine therapeutic strategies.

LLU Discipline

Biochemistry

Department

Basic Sciences

School

School of Medicine

First Advisor

Kirsch, Wolff M.

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

January 2010

Date (Title Page)

12-1-2010

Language

English

Library of Congress/MESH Subject Headings

Alzheimer's Disease; Biochemistry; Metals

Subject - Local

Transition metals; Cerebral Amyloid Angiopathy; Brain metals homeostasis; Brain iron overload

Type

Dissertation

Page Count

160 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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