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!

项目摘要 ApoE 4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 星形胶质细胞ApoE是ApoE载脂蛋白、磷脂和胆固醇的复合物。的主要作用 脑中的ApoE/脂质复合物是将胆固醇和其他脂质递送到神经元和其他细胞类型， 利用率与ApoE 4形成的脂质复合物比与ApoE 2或ApoE 4形成的脂质复合物含有更少的胆固醇。 载脂蛋白E 3。ApoE 4还导致神经细胞中N-甲基-D-天冬氨酸受体（NMDAR）介导的信号传导的故障。 海马体和皮层。我们假设这些由ApoE 4引起的功能障碍可能是 通过选择性增加体内星形胶质细胞和/或神经元中的胆固醇合成来改善。 为了验证我们的假设，我们将实现三个具体目标。 具体目的1.建立一种灵敏的方法来监测星形胶质细胞的相对胆固醇合成速率 和离体海马区的神经元。(Year一） 目的2.建立重组腺相关病毒介导的诱导型基因表达载体， 在星形胶质细胞或神经元中产生胆固醇合成的选择性增加的tSREBP 2。(Year一） 具体目标3A-监测海马星形胶质细胞和神经元中的相对胆固醇合成速率 在选择性tSREBP 2基因在体内表达之前和之后离体区域发生。(Year（二） 具体目的3B-监测NMDAR依赖性突触可塑性在急性海马脑片之前和之后， 后选择性tSREBP 2基因表达发生在海马区在体内。(Year（二） !一个！