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：
10334516
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/10334516
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 Hippocampus (Brain)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 Patients Peptides Phospholipids Proteomics Risk Factors Role Signal Pathway Signal Transduction Sphingomyelins Sterols Symptoms Synapses Synaptic plasticity Testing Therapeutic Transgenic Mice Transgenic Organisms Wild Type Mouse Work abeta accumulation amyloid pathology amyloid precursor protein processing base 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.

胆固醇代谢灾难中涉及的环境和遗传因素都是被认为是阿尔茨海默氏病（AD）发展的风险因素。胆固醇的积累在AD患者和动物的受影响的大脑区域中观察到，它与特定区域有关失去突触。升高的脑胆固醇会导致认知缺陷，淀粉样蛋白-β（Aβ）的产生和聚集和tau病理学。尽管有这些观察，但控制脑胆固醇的机制在与广告相关的病理状况下对神经元的影响和对神经元的影响仍然难以捉摸。尤其，该领域缺乏关于神经元胆固醇信号通路涉及的因素的知识代谢，与AD病理的主动性和发展有关。 ATAD3A属于一个新家庭真核线粒体AAA-ATP酶。 ATAD3A调节胆固醇稳态和通过线粒体相关的ER膜（MAM）的未知机制，该膜的专门子域 ER具有脂质筏的特征，富含胆固醇和鞘磷脂。我们最近的工作证明ATAD3A通过病理二聚化，表明了功能奖励，引起了亨廷顿氏病的神经变性。我们进一步观察到ATAD3A低聚的增强在AD神经元培养中表明ATAD3A在AD发病机理中具有异常活性。我们开发了一种新型的肽抑制剂 DA1与ATAD3A结合以阻断ATAD3A二聚化。值得注意的是，通过DA1减少的持续治疗应用水平和淀粉样蛋白负荷，减弱的神经炎症和改善的短期空间记忆在5xFAD中转基因小鼠。此外，我们的蛋白质组学分析表明，通过DA1阻断ATAD3A的低聚治疗主要影响AD小鼠大脑中的胆固醇代谢途径。广告中的处理转基因小鼠改善了脑胆固醇的更换，不会影响脑磷脂水平。而且，我们表明DA1治疗降低了胆固醇伯嫩和神经元细胞中的氧化应激表达应用WT或突变体。这些发现突出了ATAD3A的低聚为先前未识别的 AD中的脑胆固醇灾难和神经退行性的机制。我们的中心假设是 ATAD3A的低聚化介导了淀粉样病理学，导致神经变性，通过损害脑胆固醇代谢。该应用的总体目标是了解ATAD3A异常 AD中的寡聚化介导的神经病理学，并揭示了AD的新型治疗靶点。在AIM 1中，我们将确定ATAD3A低聚化对脑胆固醇稳态，AD病理学和行为定义在AD小鼠中。在AIM 2中，我们将确定AD3A的单倍级是否在AD小鼠中恢复脑胆固醇稳态并减少AD病理学。在AIM 3中，我们将剖析机械 AD3A的ATAD3A低聚与脑胆固醇稳态灾难之间的联系。