Cholesterol and Sphingolipid Metabolism in Alzheimer's Disease

阿尔茨海默病中的胆固醇和鞘脂代谢

基本信息

批准号：
9132655
负责人：
Ta Yuan CHANG
金额：
$ 33.21万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9132655
关键词：
Ablation Acyl Coenzyme A Affect Alzheimer&apos s Disease Amyloid beta-Protein Animals Autophagocytosis Autophagosome Binding Proteins Brain Cell Culture Techniques Ceramides Cholesterol Cholesterol Esters Cholesterol Homeostasis Cognitive deficits Dependovirus Disease Endoplasmic Reticulum Enzymes Esterification FRAP1 gene Genetic Goals Grant Health Hepatocyte Human Human Amyloid Precursor Protein In Vitro Intestines Knowledge Laboratories Length Mammals Mediating Membrane Memory impairment Metabolism MicroRNAs Microglia Mitochondria Mus Neuraxis Neurodegenerative Disorders Neurons Organ Outcome Patients Pattern Play Protein Isoforms Proteins Proteolysis Regulatory Element Research Role Sampling Signal Transduction Sirolimus Sphingolipids Staging Sterol O-Acyltransferase Sterols Testing Therapeutic Therapeutic Uses Tissues Transcriptional Regulation Transgenic Organisms base biological adaptation to stress brain cell brain tissue combat endoplasmic reticulum stress entorhinal cortex feeding gene therapy in vivo inhibitor/antagonist knock-down knockout gene mouse model neuron loss new therapeutic target novel therapeutic intervention programs small molecule sterol O-acyltransferase 2 tau Proteins transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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 Aß1-42 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.

描述（由申请人提供）：本申请的目标是在细胞培养物和完整动物水平上提供更多证据，以支持酰基辅酶A：胆固醇酰基转移酶1（ACAT1）作为阿尔茨海默病潜在新治疗靶点的表征（ AD）治疗中，ACAT1 是一种催化游离胆固醇转化为胆固醇酯的酶，在全身组织和大脑的胆固醇稳态中发挥着重要作用。此前，我们的实验室表明，在 AD 小鼠模型中，Acat1 基因敲除（KO）可减少淀粉样变性并挽救认知缺陷。在本次资助的最后一个周期中，我们发现表达靶向 Acat1 的 microRNA 的腺相关病毒直接传递至小鼠。有症状的 AD 小鼠的大脑中，大脑淀粉样蛋白 β 和全长人类淀粉样蛋白前体蛋白的水平降低到与 Acat1 完全基因消除相似的水平。 Acat1 基因 KO 或 ACAT1 特异性抑制剂 K604 刺激自噬体形成和转录因子 EB 介导的溶酶体蛋白水解，从而导致溶酶体 Aß1-42 降解增加。ACAT1 阻断对自噬的增强作用与雷帕霉素的哺乳动物靶标无关。 mTOR）信号传导和内质网应激反应这些结果表明小胶质细胞和神经元中的 ACAT1 阻断可能。为了在细胞培养和体内水平上提供更多证据来支持 ACAT1 阻断的治疗潜力，我们在当前应用中提出了两个具体目标：具体目标 1：检验 ACAT1 阻断的假设。通过改变线粒体相关膜内富含胆固醇/富含神经酰胺的结构域来增加自噬体形成。具体目标 2：检验小胶质细胞和神经元中 ACAT1 阻断可延迟 AD 中神经元细胞丢失和记忆缺陷的假设。相关性该申请的结果将为支持一种潜在的新治疗方法提供证据，该方法以小胶质细胞和神经元中的 ACAT1 为靶标，用于 AD 治疗。