Our long-term research interest is to provide mechanistic links between cellular lipid metabolism and neuropathology. In a new manuscript (included in the Appendix) and in the PRELIMINARY STUDIES section, we describe the following leads: 1. We show that genetic inactivation of acyl-CoA: cholesterol acyltransferase 1 (ACAT1) increases 24(S)-hydroxycholesterol content, reduces cholesterol synthesis in the brain, and ameliorates amyloid pathology in the triple transgenic Alzheimer's mice (AD mice). 2. We show that the cholesterol content, the mRNA of SREBP2 (the transcription factor that controls genes involved in cholesterol biosynthesis), the mRNA of HMGR (the rate-limiting enzyme in cholesterol biosynthesis), and the mRNAs of two interacting transcription factors, serum response factor (SRF) and myocardin (MYOCD) are elevated in the AD mice compared to nontransgenic mice. Based on these leads, in the current proposal, we design experiments to test two hypotheses. The first is to test whether inactivating the gene that encodes the cholesterol esterification enzyme ACAT1 in the brain has therapeutic value for treating AD. The second is to test if specific sphingolipid(s) mediate the action of amyloid beta peptide 1-42 (Abeta1-42) by stimulating cholesterol biosynthesis in the brain. We enlist three specific aims:
Specific Aim 1 : To test the effect of inactivating the enzyme 24(S)-hydroxylase CYP46A1, on Acat1-/- (A1-) mediated modulations on hAPP, HMGR and ABCA1 in AD mice neurons.
Specific Aim 2 : To test the effect of inactivating Acat1 in AD mouse brains at different time during life.
Specific Aim 3 : To study the effects of Abeta1-42 on cholesterol and sphingolipid metabolism in primary neurons and astrocytes.

Public Health Relevance

Alzheimer's disease (AD) causes memory loss and cognitive deficits in the elderly, and is the most prevalent neurodegenerative disease in developed countries. Abnormalities in cellular lipid metabolism have been implicated in AD. The outcomes of this proposal may lead to novel, lipid metabolism-based therapies to slow down the progression of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG037609-01
Application #
7946861
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Petanceska, Suzana
Project Start
2010-08-15
Project End
2015-07-31
Budget Start
2010-08-15
Budget End
2011-07-31
Support Year
1
Fiscal Year
2010
Total Cost
$323,900
Indirect Cost
Name
Dartmouth College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
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
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
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
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
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; 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
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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