The processing of amyloid precursor protein (APP) by - and -secretases produces amyloid (A) peptide, the principal component of the neuritic plaques found in Alzheimers disease (AD) pathology. The enzyme -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 -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 A-related peptides.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/955 |
| Date | 06 1900 |
| Creators | Kodam, Anitha |
| Contributors | Kar, Satyabrata (Departments of Medicine (Neurology) and Psychiatry), Greenshaw, Andrew J. (Department of Psychiatry), Baker, Glen B. (Department of Psychiatry), Giuliani, Fabrizio (Department of Medicine (Neurology)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 4467125 bytes, application/pdf |
| Relation | Kodam A, Neurobiol Aging. (2008), http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T09-4MT54Y8-3&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c2ca4bfcc338f18a07a94ad8288a45d7, Vetrivel KS, Kodam A, Neurobiol Dis. (2008), http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639720/?tool=pubmed |
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