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Mechanisms of Alzheimer`s Disease Pathogenesis

by
Jonathan Sedeyn
Bachelor of Science, 2006
The Richard Stockton College of New Jersey

Thesis Advisor: Venkateswar Venkataraman, Ph.D.

Cell and Molecular Biology Program

Science Center, Room 290

Friday, April 30, 2010
10 am


Abstract

Alzheimer’s disease (AD) is a progressive neurological disease, mainly of the elderly, that is hallmarked by cognitive decline resulting from neurological death. However the mechanism by which AD occurs is unknown. We propose a multi-hit hypothesis for the onset and progression of AD. Two important hits in this scheme are: a breakdown in the blood brain barrier (BBB) and elevation of Abeta42 levels in the brain. This thesis presents findings on these two major aspects of AD pathogenesis. One consequence of BBB breakdown is the extrusion of the potent inflammatory mediator histamine. While known to contribute to BBB breakdown when used in vivo, data does not exist as to histamines’ effectiveness in generating other pathologies consistent with AD in vitro. Results presented here demonstrate that treatment with histamine (both in vitro and in vivo) results in a breakdown of the BBB, astrocyte activation, and the initiation of a neuronal damage response – all hallmarks of AD. With respect to Abtea42, we hypothesize that neurons may be selected for death based on the composition of the membrane guanylate cyclase signaling pathway that they express. Through the use of PCR and IHC, we have demonstrated the presence and location of the components of this signaling system within pyramidal neurons of the hippocampus – the first neurons to die in AD. The results highlight a role for calcium signaling, both with histamine and Abeta42, in the onset and progression of AD.


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