Date of Award

1-1-2010

Document Type

Thesis

Degree Name

M.S.

Department

Biological Sciences

First Advisor

Daniel A. Linseman

Abstract

Down syndrome (DS) is the most common genetic form of cognitive disability and is caused by trisomy of chromosome 21. Within chromosome 21 is the gene, amyloid precursor protein (APP). Proteolysis of APP into toxic and aggregate-prone, beta-amyloid fragments underlies the pathophysiology of Alzheimer's disease (AD). Individuals with DS develop the neuropathology that can be diagnosed as AD; however, the role of APP overexpression in this comorbidity is presently unclear. Here, we elucidated the mechanism of cell death induced by overexpression of wild type APP. Chinese hamster ovary cells transfected with a DsRed-APP fusion construct displayed caspase-3 activation and nuclear fragmentation indicative of apoptosis. APP-induced apoptosis was blocked by a pan-caspase inhibitor, (BOC), glutathione (GSH), or co-expression of Bcl-2. APP caused depletion of mitochondrial GSH, induced opening of the permeability transition pore, and triggered cytochrome c release. Each of these events was inhibited by GSH but was unaffected by BOC indicating that they were oxidative stress-dependent and upstream of caspases. We conclude that APP overexpression is sufficient to cause mitochondrial oxidative stress and intrinsic apoptosis. We are currently examining if a similar cell death pathway is induced by APP in neuronal cells. Our data are consistent with an increased expression of APP being a likely contributor to neuron death in DS. Thus, decreasing APP-induced oxidative stress and apoptosis may be beneficial in reducing the comorbid phenotype of DS patients afflicted with AD.

Provenance

Recieved from ProQuest

Rights holder

Matthew Gabriel Bartley

File size

82 p.

File format

application/pdf

Language

en

Discipline

Neurosciences

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