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：
9272296
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/9272296
关键词：
Ablation Acyl Coenzyme A Affect Alzheimer&apos s Disease Alzheimer&apos s disease model 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 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 Sterol O-Acyltransferase Sterols Testing Therapeutic Therapeutic Uses Tissues Transcriptional Regulation Transgenic Organisms biological adaptation to stress brain cell 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 public health relevance small molecule sterol O-acyltransferase 1 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（由应用提供）：当前应用的目的是在细胞培养和完整的动物水平上提供更多证据，以支持酰基-COA的表征：胆固醇酰基转移酶1（ACAT1），作为阿尔茨海默氏病（AD）治疗的潜在新治疗靶标。 ACAT1是一种酶，可催化游离胆固醇向胆固醇酯的转化，并且在系统性组织和大脑中胆固醇稳态中起重要作用。以前，我们的实验室表明，在用于AD的小鼠模型中，ACAT1的基因基因敲除（KO）降低了淀粉样病，并反应了认知缺陷。在这笔赠款的最后一个周期中，我们表明，靶向ACAT1的腺相关病毒直接传递到有症状的AD小鼠的大脑中，降低了脑淀粉样蛋白-beta和全长淀粉样前体蛋白的水平，类似于与ACAT1的完全普通消融相似的水平。我们还表明，在小胶质细胞和神经元中，ACAT1基因KO或ACAT1特异性抑制剂K604刺激自噬体的形成和转录因子EB介导的溶酶体蛋白水解，从而导致溶酶体Aß1-42降解的增加。 ACAT1阻塞对自噬的增强作用与雷帕霉素（MTOR）信号传导和内质网应激反应的哺乳动物靶标无关。结果表明，小胶质细胞和神经元中的ACAT1阻塞可能在AD的治疗中有效。为了在细胞培养和体内水平上提供更多证据以支持ACAT1阻塞的治疗潜力，我们在当前应用中提出了两个具体目标：具体目的1：测试ACAT1阻滞通过改变胆固醇/ceramide富含胆固醇/陶瓷含量的富含胆固醇/陶瓷型域的假说，在线粒体 - 富含胆固醇/陶瓷的域。特定目的2：测试以下假设：小胶质细胞和神经元中的ACAT1阻塞延迟了神经元细胞的损失，并且记忆在AD中定义。相关性本应用的结果将提供证据，以支持小胶质细胞和神经元中ACAT1的潜在新治疗方法进行AD治疗。