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ACAT1 blockage stimulates autophagy to emeliorate Alzheimer's disease / by Yohei Shibuya

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Author	Shibuya, Yohei
Title	ACAT1 blockage stimulates autophagy to emeliorate Alzheimer's disease / by Yohei Shibuya
Date	2015
Abstract	Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the aging population. Currently, there is no cure for AD. The hallmark of AD consists of extracellular amyloid plaques, mainly composed of amyloid beta (Ab) peptides (especially Ab1-42), and neurofibrillary tangles, mainly composed of hyperphosphorylated tau. Ab and tau can interact with each other synergistically to trigger neurotoxicity. Autophagy is a lysosomal degradation process that mediates the cellular clearance of misfolded/aggregated proteins/peptides including Ab and tau. Malfunctions in autophagy have been observed in several neurodegenerative diseases, and it has been proposed that promoting cellular autophagy may be an effective strategy to treat AD and other related neurodegenerative diseases. Acyl-CoA: cholesterol acyltransferase (ACAT) converts free cholesterol to cholesteryl esters and plays important roles in cellular cholesterol homeostasis. Previous work from this and other laboratories showed that blocking ACAT1 decreases amyloidopathy in cell culture and in mouse models for AD. These studies suggest the potential therapeutic use of ACAT1 blockage to treat AD. However, the mechanism(s) responsible for the beneficial actions of blocking ACAT1 to treat AD remained not well understood. Microglia play essential roles in the proteolytic clearance of Aβ peptides. In Chapter 2, I show that Acat1 gene KO in mouse increases phagocytic uptake of oligomeric Aβ1–42 and stimulates lysosomal Aβ1–42 degradation in cultured microglia and in vivo. Additional results show that Acat1 gene KO or a specific ACAT1 inhibitor K604 stimulates autophagosome formation and transcription factor EB-mediated lysosomal proteolysis. In Chapter 3, I show that in murine neuroblastoma cells ectopically expressing human tau, and in primary neurons isolated from triple transgenic AD mice, ACAT1 blockage increases autophagosome formation, increases lysosomal enzyme gene expression, and decreases human tau protein content, without affecting endogenous mouse tau protein content. A common event that occurs in several prevalent neurodegenerative diseases, is the prominent presence of specific misfolded/aggregated proteins/peptides in certain regions of the CNS. The cellular clearance of misfolded/aggregated proteins/peptides involves autophagy-mediated lysosomal proteolysis. My results suggest that blocking ACAT1 may provide a novel way to benefit several neurodegenerative diseases in general.
Description	1 online resource (xv, 174 pages) : illustrations (some color)
Format	application/pdf
College	Geisel School of Medicine at Dartmouth -- Department of Biochemistry.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1922

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