The goal of the current application is to provide more evidence at the cell culture and intact animal levels to support the characterization of acyl-CoA: cholesterol acyltransferase1 (ACAT1) as a potential new therapeutic target for Alzheimer's disease (AD) treatment. ACAT1 is an enzyme that catalyzes the conversion of free cholesterol to cholesterol esters, and that plays an important role in cholesterol homeostasis in systemic tissues and the brain. Previously, our laboratory showed that in a mouse model for AD, gene knockout (KO) of Acat1 decreased amyloidopathy and rescued cognitive deficits. During the last cycle of this grant, we showed that adeno-associated viruses expressing microRNAs targeting Acat1 delivered directly to the brains of symptomatic AD mice decreased the levels of brain amyloid-beta and full-length human amyloid precursor protein to levels similar to complete genetic ablation of Acat1. We also showed that in microglia and neurons, Acat1 gene KO or an ACAT1-specific inhibitor K604 stimulated autophagosome formation and transcription factor EB-mediated lysosomal proteolysis, thereby resulting in an increase in lysosomal A1-42 degradation. The enhancing effect of ACAT1 blockage on autophagy was independent of mammalian target of rapamycin (mTOR) signaling and the endoplasmic reticulum stress response. These results suggest that ACAT1 blockage in microglia and neurons may be effective in the treatment of AD. To provide more evidence at the cell culture and in vivo levels to support the therapeutic potential of ACAT1 blockage, we propose two specific aims in the current application:
Specific Aim 1 : To test the hypothesis that ACAT1 blockage increases autophagosome formation by altering the cholesterol-rich/ceramide-rich domain within the mitochondrial- associated membrane.
Specific Aim 2 : To test the hypothesis that ACAT1 blockage in microglia and neurons delays neuronal cell loss and memory deficits in AD. Relevance The outcome of this application will offer evidence to support a potential new therapeutic approach to target ACAT1 in microglia and neurons for AD treatment.

Public Health Relevance

Alzheimer's disease (AD) is a major neurodegenerative disease. Currently, there is no cure for AD. Acyl-CoA: cholesterol acyltransferase1 (ACAT1) is an enzyme that plays an important role in cholesterol homeostasis in many tissues, including the brain. Recent evidence from our laboratory shows that blocking ACAT1 activity can ameliorate brain cells that are affected by AD. This application seeks to provide more evidence at the cell culture level and the intact animal level to support the characterization of ACAT1 as a potential new therapeutic target for AD treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037609-09
Application #
9486807
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Petanceska, Suzana
Project Start
2010-08-15
Project End
2020-04-30
Budget Start
2018-06-15
Budget End
2019-04-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Chang, Ta-Yuan; Yamauchi, Yoshio; Hasan, Mazahir T et al. (2017) Cellular cholesterol homeostasis and Alzheimer's disease. J Lipid Res 58:2239-2254
Chang, Ta-Yuan; Chang, Catherine (2017) ApoE and Lipid Homeostasis in Alzheimer's Disease: Introduction to the Thematic Review Series. J Lipid Res 58:823
Wang, Yong-Jian; Bian, Yan; Luo, Jie et al. (2017) Cholesterol and fatty acids regulate cysteine ubiquitylation of ACAT2 through competitive oxidation. Nat Cell Biol 19:808-819
Yamauchi, Yoshio; Yokoyama, Shinji; Chang, Ta-Yuan (2017) Methods for Monitoring ABCA1-Dependent Sterol Release. Methods Mol Biol 1583:257-273
Guo, Dongqing; Zhang, Xiaowei; Li, Qin et al. (2016) The ACAT2 expression of human leukocytes is responsible for the excretion of lipoproteins containing cholesteryl/steryl esters. Acta Biochim Biophys Sin (Shanghai) 48:990-997
Guo, Dongqing; Lu, Ming; Hu, Xihan et al. (2016) Low-level expression of human ACAT2 gene in monocytic cells is regulated by the C/EBP transcription factors. Acta Biochim Biophys Sin (Shanghai) 48:980-989
Shibuya, Yohei; Niu, Zhaoyang; Bryleva, Elena Y et al. (2015) Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage. Neurobiol Aging 36:2248-2259
Rogers, Maximillian A; Liu, Jay; Song, Bao-Liang et al. (2015) Acyl-CoA:cholesterol acyltransferases (ACATs/SOATs): Enzymes with multiple sterols as substrates and as activators. J Steroid Biochem Mol Biol 151:102-7
Yamauchi, Yoshio; Iwamoto, Noriyuki; Rogers, Maximillian A et al. (2015) Deficiency in the Lipid Exporter ABCA1 Impairs Retrograde Sterol Movement and Disrupts Sterol Sensing at the Endoplasmic Reticulum. J Biol Chem 290:23464-77
Shibuya, Yohei; Chang, Catherine Cy; Chang, Ta-Yuan (2015) ACAT1/SOAT1 as a therapeutic target for Alzheimer's disease. Future Med Chem 7:2451-67

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