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Cellular and molecular mechanisms by which specific GSK3 inhibition affects the processing of the Amyloid Precursor Protein

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Title: Cellular and molecular mechanisms by which specific GSK3 inhibition affects the processing of the Amyloid Precursor Protein
Authors: Parr, Callum John Christopher
Item Type: Thesis or dissertation
Abstract: Alzheimer’s disease (AD) has long been associated with altered activity of the serine/threonine kinases, Glycogen Synthase Kinase-3 (GSK3) isozymes, which are proposed to contribute to both neurofibrillary tangles and amyloid plaque formation. While the molecular links between GS3K and tau pathology are well established, the molecular basis by which GSK3 affects the formation of amyloid-β (Aβ) remains unknown. The aim of this investigation was to identify the underlying mechanisms by which inhibition of GSK3 affects the processing of the amyloid precursor protein (APP). To this end various methods were employed to alter the basal activity of the GSK3 enzyme in N2a cells, a mouse neuroblastoma cell-line, overexpressing the Swedish variant of APP. Specific perturbation of GSK3 activity leads to an alteration in APP processing and Aβ production, something that until now, was seen as controversial. Specific pharmacological inhibition of GSK3 resulted in a decrease in activity, expression and transcription of BACE1, which is the main enzyme responsible for Aβ generation. Activation of the canonical Wnt pathway, which is associated with negative regulation of GSK3, reproduced the previous findings and led to reduction in transcription and expression of BACE1. Furthermore, specific pharmacological GSK3 inhibition and GSK3α/β knockdown enhanced full-length APP degradation via an increase in the number of lysosomes. This induction of the lysosomal/autophagy pathway was associated with the effect of specific GSK3 inhibition on the nuclear translocation of transcription factor EB (TFEB), which is a master regulator of lysosomal biogenesis. All together, GSK3, in addition to being associated with hyperphosphorylation of tau, can also influence Aβ generation through regulating BACE1 expression and the homeostatic turnover of APP. This data reinforces the hypothesis that GSK3 could be a therapeutic target for AD as it is shown to be a central signalling node in the pathogenesis of the disease.
Issue Date: 2012
Date Awarded: Aug-2012
URI: http://hdl.handle.net/10044/1/9991
DOI: https://doi.org/10.25560/9991
Supervisor: Sastre, Magdalena
Sponsor/Funder: Imperial College London
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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