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Regulation of the metabolism of the Alzheimer's amyloid precursor protein by contactin 5 and BIN1

Glennon, Elizabeth Bernadette Claire (2012) Regulation of the metabolism of the Alzheimer's amyloid precursor protein by contactin 5 and BIN1. PhD thesis, University of Leeds.

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Alzheimer’s disease (AD) is a progressive form of dementia, which currently has no cure. The metabolism of the amyloid precursor protein (APP) is an important determinant in the development of AD. APP is proteolytically processed either in the amyloidogenic pathway, generating the AD-causing amyloid-beta (Aβ) peptide, or in the non-amyloidogenic pathway which prevents the generation of Aβ. The role of four different proteins, BIN1, contactin 5, neurofascin and Thy-1, in the regulation of APP proteolytic processing was investigated. Contactin 5, neurofascin and Thy-1 have been shown to interact with APP, whereas BIN1 has been genetically related to AD by genome-wide association studies. Over-expression of each protein in cell lines showed that BIN1 and contactin 5, but not neurofascin or Thy-1, regulate the production of Aβ. Contactin 5 over-expression prevented Aβ generation by inhibiting cleavage of APP by the γ-secretase. Western blots of human brain samples showed that contactin 5 levels in the brain are not altered during aging or in AD. BIN1 over-expression decreased APP levels, and decreased Aβ, whereas BIN1 knockdown increased APP, suggesting that BIN1 redirects APP from processing in the amyloidogenic pathway to a compartment of the cell where it is degraded. BIN1 did not alter either Aβ uptake, or the endocytosis or cell surface levels of APP. BIN1 levels were shown to be reduced in the brain during aging and in AD. This has led to the hypothesis that during aging and AD, BIN1 levels decrease, so more APP is trafficked into the amyloidogenic pathway rather than being degraded, resulting in more Aβ generation so increasing the risk of developing AD. This is the first time a mechanism for the role of BIN1 in AD has been suggested.

Item Type: Thesis (PhD)
ISBN: 978-0-85731-306-5
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds) > Institute for Molecular and Cellular Biology (Leeds)
Identification Number/EthosID: uk.bl.ethos.568132
Depositing User: Repository Administrator
Date Deposited: 14 Mar 2013 12:57
Last Modified: 07 Mar 2014 11:24
URI: http://etheses.whiterose.ac.uk/id/eprint/3752

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