Cholesterol and Sphingolipid Metabolism in Alzheimer's Disease

阿尔茨海默病中的胆固醇和鞘脂代谢

• 批准号: 8699618
• 负责人: Ta Yuan CHANG
• 金额: $ 31.13万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699618
• 关键词: Abbreviations; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Astrocytes; Binding Proteins; Biological Models; Brain; C-terminal; CYP46A1 gene; Cells; Ceramidase; Ceramides; Cholesterol; Cognitive deficits; Dementia; Developed Countries; Disease Progression; Dose; Elderly; Enzyme-Linked Immunosorbent Assay; Enzymes; Esterification; Genes; Genetic; Hippocampus (Brain); Hydroxycholesterols; Hydroxymethylglutaryl-CoA reductase; Immunoprecipitation; Individual; Late Onset Alzheimer Disease; Lead; Life; Link; Lysophospholipids; Manuscripts; Mediating; Memory Loss; Messenger RNA; Metabolism; Mixed Function Oxygenases; Monitor; Mus; Neurodegenerative Disorders; Neurons; Outcome; Peptides; RNA Interference; Recombinant adeno-associated virus (rAAV); Regulatory Element; Research; Serum Response Factor; Site; Small Interfering RNA; Sphingolipids; Sphingomyelinase; Sphingomyelins; Sphingosine; Squalene Synthetase; Sterol O-Acyltransferase; Sterols; Testing; Thalamic structure; Therapeutic; Time; Transgenic Organisms; acid sphingomyelinase; amyloid pathology; base; cholesterol biosynthesis; design; familial Alzheimer disease; interest; lipid metabolism; lysophosphatidic acid; myocardin; neuropathology; novel; research study; secretase; sphingosine 1-phosphate; sphingosine phosphorylcholine; sterol O-acyltransferase 1; transcription factor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：我们的长期研究兴趣是提供细胞脂质代谢和神经病理学之间的机制联系。在一份新手稿（包含在附录中）和初步研究部分中，我们描述了以下线索：1.我们表明，酰基辅酶A的基因失活：胆固醇酰基转移酶1（ACAT1）增加了24（S）-羟基胆固醇含量，减少了大脑中的胆固醇合成，并改善了三重转基因中的淀粉样蛋白病理学 阿尔茨海默病小鼠（AD 小鼠）。 2. 我们发现，与 AD 小鼠相比，AD 小鼠的胆固醇含量、SREBP2（控制胆固醇生物合成相关基因的转录因子）的 mRNA、HMGR（胆固醇生物合成中的限速酶）的 mRNA 以及两个相互作用的转录因子（血清反应因子（SRF）和心肌素（MYOCD））的 mRNA 均升高。 非转基因小鼠。基于这些线索，在当前的提案中，我们设计了实验来检验两个假设。首先是测试灭活大脑中编码胆固醇酯化酶ACAT1的基因对于治疗AD是否具有治疗价值。第二个是测试特定的鞘脂是否通过刺激大脑中的胆固醇生物合成来介导淀粉样蛋白 β 肽 1-42 (Abeta1-42) 的作用。我们列出了三个具体目标： 具体目标 1：测试 24(S)-羟化酶 CYP46A1 失活对 Acat1-/- (A1-) 介导的 AD 小鼠神经元 hAPP、HMGR 和 ABCA1 调节的影响。具体目标2：测试在生命中不同时间灭活Acat1对AD小鼠大脑的影响。具体目标3：研究Abeta1-42对原代神经元和星形胶质细胞中胆固醇和鞘脂代谢的影响。