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Role of brain lipid metabolism in Alzheimer's disease

脑脂质代谢在阿尔茨海默病中的作用

基本信息

批准号：
10532713
负责人：
XIN QI
金额：
$ 60.38万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532713
关键词：
AD transgenic mice ATP phosphohydrolase Abeta synthesis Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloidosis Animal Model Animals Area Attenuated Autopsy Behavioral Binding Biochemical Biogenesis Biological Assay Brain Cell Culture Techniques Cells Cholesterol Cholesterol Homeostasis Cognitive deficits Data Development Dimerization Disease Progression Embryo Enzymes Event Exposure to Family Gene Mutation Genes Genetic Goals Heterozygote Hippocampus Huntington Disease Impairment Injury Knock-in Mouse Knock-out Knockout Mice Knowledge Link Lipids Measures Mediating Membrane Membrane Microdomains Metabolic Pathway Mitochondria Molecular Mus Mutant Strains Mice Nerve Degeneration Neurological status Neurons Oxidative Stress Pathogenesis Pathologic Pathology Pathway interactions Peptides Phospholipids Proteomics Risk Factors Role Signal Induction Signal Pathway Sphingomyelins Sterols Symptoms Synapses Synaptic plasticity Testing Therapeutic Transgenic Mice Transgenic Organisms Wild Type Mouse Work abeta accumulation amyloid pathology amyloid precursor protein processing brain dysfunction cell injury cholesterol control cholesterol trafficking density dimer gain of function improved inhibitor insight knock-down lipid metabolism mind control mutant mutant mouse model neuroinflammation neuron development neuronal survival neuropathology new therapeutic target novel overexpression spatial memory tau Proteins

项目摘要

Both environmental and genetic factors involved in the disturbance of cholesterol metabolism have been suggested as risk factors for the development of Alzheimer's disease (AD). Accumulation of cholesterol has been observed in affected brain areas from AD patients and animals, and it is associated with region-specific loss of synapses. Elevated brain cholesterol causes cognitive deficits, amyloid-β (Aβ) production and aggregation, and tau pathology. Despite these observations, the mechanisms that govern brain cholesterol homeostasis and influence on neurons under AD-related pathological conditions remain elusive. In particular, the field lacks knowledge on the factors that are involved in the signaling pathways of neuronal cholesterol metabolism, related to the initiation and development of AD pathology. ATAD3A belongs to a new family of eukaryotic mitochondrial AAA-ATPases. ATAD3A regulates cholesterol homeostasis and trafficking via an unknown mechanism at the mitochondria-associated ER membrane (MAM), a specialized subdomain of the ER that has the features of a lipid raft and is rich in cholesterol and sphingomyelin. Our recent work demonstrated that ATAD3A, via pathological dimerization, showed a gain-of-function that caused neurodegeneration in Huntington's disease. We further observed an enhancement of ATAD3A oligomerization in AD neuronal culture, in AD transgenic mouse brains and in AD patient postmortem hippocampus, suggesting an aberrant activity of ATAD3A in the pathogenesis of AD. We developed a novel peptide inhibitor DA1 that binds to ATAD3A to block ATAD3A dimerization. Notably, sustained treatment with DA1 reduced APP level and amyloid load, attenuated neuro-inflammation and improved short-term spatial memory in 5XFAD transgenic mice. Further, our proteomic analysis suggests that blocking ATAD3A oligomerization by DA1 treatment mainly influenced the cholesterol metabolic pathway in AD mouse brains. The treatment in AD transgenic mice improved brain cholesterol turnover and did not affect brain phospholipids levels. Moreover, we showed that DA1 treatment reduced cholesterol burden and oxidative stress in neuronal cells stably expressing APP wt or mutant. These findings highlight ATAD3A oligomerization as a previously unidentified mechanism underlying brain cholesterol disturbance and neurodegeneration in AD. Our central hypothesis is that ATAD3A oligomerization mediates amyloid pathology, leading to neurodegeneration, by impairment of brain cholesterol metabolism. The overall goal of this application is to understand ATAD3A aberrant oligomerization-mediated neuropathology in AD, and to reveal a novel therapeutic target for AD. In Aim 1, we will determine the impact of ATAD3A oligomerization on brain cholesterol homeostasis, AD pathology and behavioral deficits in AD mice. In Aim 2, we will determine whether haplosufficiency of ATAD3A in AD mice restores brain cholesterol homeostasis and reduces AD pathology. In Aim 3, we will dissect the mechanistic links between ATAD3A oligomerization and disturbance in brain cholesterol homeostasis in AD.

胆固醇代谢紊乱的环境和遗传因素都已被研究。被认为是阿尔茨海默病（AD）发展的危险因素。胆固醇的积累在AD患者和动物的受影响脑区中观察到，并且与区域特异性失去突触脑胆固醇升高会导致认知缺陷、β淀粉样蛋白（Aβ）生成和聚集和tau病理学。尽管有这些观察结果，在AD相关的病理条件下对神经元的稳态和影响仍然是难以捉摸的。特别是，该领域缺乏对参与神经元胆固醇信号通路的因素的知识代谢，与AD病理的发生和发展有关。ATAD 3A属于一个新家族，真核线粒体AAA-ATP酶。ATAD 3A通过一种新的途径调节胆固醇稳态和运输。在ESTA相关ER膜（MAM）的未知机制，一个专门的亚域， ER具有脂筏的特征，富含胆固醇和鞘磷脂。我们最近的工作证明ATAD 3A通过病理性二聚化表现出功能获得，导致亨廷顿舞蹈症的神经变性我们进一步观察到ATAD 3A寡聚化的增强，在AD神经元培养物、AD转基因小鼠脑和AD患者死后海马中，提示ATAD 3A在AD发病机制中的异常活性。我们开发了一种新的肽抑制剂结合ATAD 3A以阻断ATAD 3A二聚化的DA 1。值得注意的是，用DA 1持续治疗减少了 APP水平和淀粉样蛋白负荷，减轻神经炎症，改善5XFAD的短期空间记忆转基因小鼠此外，我们的蛋白质组学分析表明，通过DA 1阻断ATAD 3A寡聚化，治疗主要影响AD小鼠脑中的胆固醇代谢途径。AD的治疗转基因小鼠改善了脑胆固醇的周转，但不影响脑磷脂水平。此外，委员会认为，我们发现DA 1处理稳定地降低了神经元细胞的胆固醇负荷和氧化应激，表达APP wt或突变体。这些发现强调了ATAD 3A寡聚化是以前未鉴定的 AD脑胆固醇紊乱和神经退行性变的机制。我们的核心假设是 ATAD 3A寡聚化介导淀粉样蛋白病理学，导致神经退行性变，脑胆固醇代谢本应用程序的总体目标是了解ATAD 3A异常寡聚化介导的神经病理学在AD中的作用，并揭示AD的新治疗靶点。目标1：将确定ATAD 3A寡聚化对脑胆固醇稳态、AD病理学和 AD小鼠的行为缺陷。在目的2中，我们将确定AD小鼠中ATAD 3A的单倍性是否存在恢复脑胆固醇稳态并减少AD病理。在目标3中，我们将剖析 ATAD 3A寡聚化与AD患者脑胆固醇稳态紊乱之间的联系