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Permanent link (DOI): https://doi.org/10.7939/R3TD8G

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Cellular level/distribution of γ-secretase subunit nicastrin and its modulator p23 in the brain Open Access

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Other title
Subject/Keyword
Alzheimer’s disease
Gamma secretase modulator
p23/TMP21
Gamma secretase
Nicastrin
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Kodam, Anitha
Supervisor and department
Kar, Satyabrata (Departments of Medicine (Neurology) and Psychiatry)
Examining committee member and department
Greenshaw, Andrew J. (Department of Psychiatry)
Baker, Glen B. (Department of Psychiatry)
Giuliani, Fabrizio (Department of Medicine (Neurology))
Department
Department of Psychiatry
Specialization

Date accepted
2010-01-27T21:08:33Z
Graduation date
2010-06
Degree
Master of Science
Degree level
Master's
Abstract
The processing of amyloid precursor protein (APP) by β- and γ-secretases produces amyloid β (Aβ) peptide, the principal component of the neuritic plaques found in Alzheimer’s disease (AD) pathology. The enzyme γ-secretase is a multimeric protein consisting of presenilins-1/2 (PS1/PS2), nicastrin, anterior pharynx defective 1 (APH-1) and presenilin enhancer-2 (PEN-2). Recently it was discovered that p23, a transmembrane protein involved in intracellular protein trafficking, negatively regulates γ-secretase activity. In the present study, I evaluated the levels/expression of the nicastrin and p23 and their possible colocalization with PS1 in normal adult and developing brains. Additionally, I have studied the alterations of p23 levels in both animal model of neurodegeneration and in postmortem AD brains. Nicastrin and p23 were widely distributed throughout the brain and colocalized in all brain regions with PS1. The levels of nicastrin and p23 were relatively high at the early stages of postnatal development and then declined gradually as age increased. Interestingly, p23 level/expression was found to be altered following kainic acid-induced neurodegeneration in the adult rat brain. Additionally, p23 levels were reduced in the brains of individuals with AD. These results, taken together, suggest that both nicastrin and p23 are expressed in neurons throughout the brain and their levels decline gradually during development to reach an adult profile. Additionally, my results indicate that a decreased level of p23 may contribute to AD pathogenesis by increasing the production of Aβ-related peptides.
Language
English
DOI
doi:10.7939/R3TD8G
Rights
License granted by Anitha Kodam (rajesh9944@gmail.com) on 2010-01-27T17:06:39Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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