The role of dysregulated autophagy in Alzheimer's disease

Harris, M. N. (2017) The role of dysregulated autophagy in Alzheimer's disease. PhD, University of the West of England. Available from: http://eprints.uwe.ac.uk/29408

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Abstract/Description

Introduction: The accumulation of misfolded Aβ and phospho-tau are characteristic features of Alzheimer’s disease (AD) pathology. One of the cellular mechanisms responsible for the removal of these aggregates is autophagy, where proteins and organelles are degraded through the formation of autolysosomes. Nutrient status regulates autophagy through crosstalk between several signalling pathways including mTOR and AMPK. Under fed conditions, branched-chain amino acids (BCAAs) stimulate mTOR activity and downregulate autophagy. Conversely, under stress such as starvation, mTOR is inhibited and autophagy is initiated. In AD, autophagy is considered to be dysregulated and contributes to the build-up of misfolded proteins. As the branched-chain aminotransferase (hBCAT) proteins, which metabolise BCAAs, are significantly up-regulated in AD brain, it is important to understand if this increase impacts mTOR and autophagy. Understanding of these mechanisms will offer insight into the clearance of protein aggregates and the pathology underpinning AD. Methods: Using molecular biological investigations, western blot analysis and confocal microscopy, the impact of increased hBCAT expression in neuronal cells was determined in response to nutrient and hormonal stimuli. Results and discussion: This work demonstrates for the first time the impact of hBCAT overexpression on the autophagy and mTOR pathways. hBCAT overexpression resulted in an increase in mTOR activation, whereas autophagy was significantly increased at the lower concentrations of overexpression plasmid but decreased at the higher concentrations. Furthermore, hBCAT overexpression reduced the level of Aβ in a concentration-dependent manner. These findings indicate a concentration-dependent role for hBCAT in autophagy, consequently impacting Aβ load. The association of hBCATc with the membrane in response to insulin signalling is likely to play a role in this mechanism. Co-immunoprecipitation studies showing that PDI, the protein disulphide isomerase responsible for protein folding, and hBCAT interact offer additional novel roles for hBCAT in protein folding. Although this mechanism requires further interpretation, we anticipate that through its redox-active CXXC motif, hBCAT operates as a bifunctional enzyme switching between regulation of metabolic pathways such as mTOR and protein folding pathways, involving PDI. Developing the understanding of hBCAT’s role in the brain, in the context of AD, reveals new insights into the dysregulated pathways such as mTOR and autophagy. A greater understanding of these pathways has the potential to provide new therapeutic strategies in the future.

Item Type:Thesis (PhD)
Uncontrolled Keywords:Alzheimer's disease, branched-chain aminotransferase autophagy
Faculty/Department:Faculty of Health and Applied Sciences > Department of Applied Sciences
ID Code:29408
Deposited By: M. Harris
Deposited On:16 Mar 2017 15:58
Last Modified:25 Sep 2017 06:17

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