Generation of Stable Cell Lines Expressing Notch and Presenilin: Insights into the Function of Presenilin in Notch Signaling and Alzheimer's Disease
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Authors
Bingham, Sarah
Issue Date
2000
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Familial early-onset Alzheimer's disease (FAD) affects approximately 10% of all cases
of Alzheimer's disease. F AD is associated with dementia and neurofibrillary tangles, but its
most distinctive feature is the deposition of extracellular amyloid plaques. FAD is
characterized by the autosomal dominant inheritance of mutant genes encoding the amyloid
precursor protein (APP), presenilin 1 (PS1), and presenilin2 (PS2), which, in mutated forms,
increase the formation of amyloid-𝛽 (A𝛽) plaques. These plaques are produced from the
result of aberrantly processed APP molecules. Presenilins primarily reside in the endoplasmic
reticulum and are thought to regulate protein trafficking. But, how mutated presenilins
increase A𝛽 deposition is unknown. Known substrates of presenilin are the LIN12/Notch
transmembrane receptors, which control cell fate decisions in diverse organisms. Like APP,
Notch is a transmembrane protein that also undergoes proteolytic processing. Therefore,
investigation into the regulation of Notch processing by presenilin can potentially offer more
insight into presenilin' s role in Alzheimer's disease and how it affects normal molecular APP
processing and aberrant APP processing leading to amyloid plaque formation. In this study,
our initial goal was to generate stable cell lines expressing Notch and presenilin that would
provide viable cell culture models for Notch and presenilin interactions. These interactions
would then be examined by studying the formation of Notch cleavage products. We were
able to generable these novel stable cell lines. Additionally, our analysis of Notch processing
indicates that it occurs both in the presence and absence of presenilin and generates two
fragments, the functional heterodimer and an intracellular domain thought to translocate to the
nucleus to modulate gene expression. Overall, our data support a need for further
investigation into our stable cell lines and the regulation of Notch by presenilin.
With honors.
With honors.
Description
vii, 51 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.