Rescuing the ApoE4 genotype by activating sterol biosynthesis in the CNS

通过激活中枢神经系统中的甾醇生物合成来拯救 ApoE4 基因型

• 批准号: 9360281
• 负责人: Ta Yuan CHANG
• 金额: $ 18.68万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360281
• 关键词: Acute; Alzheimer' s Disease; Apolipoprotein E; Apolipoproteins; Astrocytes; Biomedical Research; Brain; Brain region; Cholesterol; Communities; Complex; Disease; Gene Expression; Genotype; Health; Hippocampus (Brain); Human; Late Onset Alzheimer Disease; Lipids; Mediating; Monitor; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neurons; Outcome; Patients; Phospholipids; Procedures; Recombinant adeno-associated virus (rAAV); Risk Factors; Role; Slice; Sterol Biosynthesis Pathway; Synaptic plasticity; Testing; apolipoprotein E-3; apolipoprotein E-4; cell type; cholesterol biosynthesis; in vivo; inducible gene expression; receptor-mediated signaling

PROJECT SUMMARY ApoE4 is a major risk factor for late onset Alzheimer’s disease. In the CNS, ApoE is mainly produced by astrocytes. ApoE is a complex of ApoE apolipoprotein, phospholipids, and cholesterol. A major role of the ApoE/lipid complex in the brain is to deliver cholesterol and other lipids to neurons and other cell types for utilization. The lipid complex formed with ApoE4 contains less cholesterol than those formed with ApoE2 or ApoE3. ApoE4 also leads to malfunctions in N-methyl-D-aspartate receptor (NMDAR) mediated signaling in the hippocampus and in the cortex. We hypothesize that these malfunctions caused by ApoE4 can be ameliorated by selectively increasing cholesterol synthesis in the astrocytes and/or in the neurons in vivo. To test our hypothesis, we will carry out three specific aims. Specific Aim 1.To establish a sensitive procedure to monitor relative cholesterol synthesis rates in astrocytes and neurons of the hippocampal region ex vivo. (Year one) Specific Aim 2.To establish a recombinant adeno-associated virus-mediated inducible gene expression in tSREBP2 that produces selective increase in cholesterol synthesis in astrocytes or in neurons. (Year one) Specific Aim 3A-To monitor relative cholesterol synthesis rates in astrocytes and neurons in the hippocampal region ex vivo before and after selective tSREBP2 gene expression occurs in vivo. (Year two) Specific Aim 3B-To monitor NMDAR dependent synaptic plasticity in acute hippocampal slices before and after selective tSREBP2 gene expression occurs in the hippocampal region in vivo. (Year two) ! 1!

项目概要 ApoE4是迟发性阿尔茨海默病的主要危险因素，在中枢神经系统中，ApoE主要由中枢神经系统产生。 ApoE 是 ApoE 载脂蛋白、磷脂和胆固醇的复合物。 大脑中的 ApoE/脂质复合物将胆固醇和其他脂质输送到神经元和其他细胞类型 由 ApoE4 形成的脂质复合物含有比由 ApoE2 或 ApoE2 形成的脂质复合物更少的胆固醇。 ApoE3.ApoE4 也会导致 N-甲基-D-天冬氨酸受体 (NMDAR) 介导的信号传导功能障碍。 我们发现，这些功能障碍可能是由 ApoE4 引起的。 通过选择性地增加星形胶质细胞和/或体内神经元中的胆固醇合成来改善。 为了检验我们的假设，我们将实现三个具体目标。 具体目标 1.建立一个敏感的程序来监测星形胶质细胞中的相对胆固醇合成率 和离体海马区的神经元（第一年）。 具体目标2.建立重组腺相关病毒介导的诱导基因表达 tSREBP2 选择性增加星形胶质细胞或神经元中的胆固醇合成（第一年）。 具体目标 3A-监测海马星形胶质细胞和神经元的相对胆固醇合成率 体内发生选择性 tSREBP2 基因表达之前和之后的离体区域（第二年）。 具体目标 3B-监测急性海马切片之前和之后的 NMDAR 依赖性突触可塑性 在体内海马区发生选择性 tSREBP2 基因表达后（第二年）。 ！ 1！