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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.

环境和遗传因素均与胆固醇代谢紊乱有关建议作为阿尔茨海默病（AD）发展的危险因素。胆固醇的积累有在 AD 患者和动物受影响的大脑区域中观察到，它与区域特异性相关突触丧失。脑胆固醇升高会导致认知缺陷、β-淀粉样蛋白 (Aβ) 产生和聚集和 tau 病理学。尽管有这些观察结果，控制大脑胆固醇的机制 AD 相关病理条件下的稳态和对神经元的影响仍然难以捉摸。尤其，该领域缺乏对参与神经元胆固醇信号传导途径的因素的了解代谢，与 AD 病理的发生和发展有关。 ATAD3A 属于一个新家族真核线粒体 AAA-ATP 酶。 ATAD3A 通过调节胆固醇稳态和运输线粒体相关内质网膜（MAM）的未知机制，这是线粒体的一个专门亚结构域 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 ATAD3A 通过病理二聚化表现出功能获得性，导致亨廷顿病中的神经变性。我们进一步观察到 ATAD3A 寡聚化的增强在 AD 神经元培养物、AD 转基因小鼠大脑和 AD 患者死后海马体中，提示 ATAD3A 在 AD 发病机制中存在异常活性。我们开发了一种新型肽抑制剂 DA1 与 ATAD3A 结合以阻止 ATAD3A 二聚化。值得注意的是，持续使用 DA1 治疗可减少 5XFAD 中的 APP 水平和淀粉样蛋白负荷、减轻神经炎症并改善短期空间记忆转基因小鼠。此外，我们的蛋白质组分析表明，通过 DA1 阻断 ATAD3A 寡聚化治疗主要影响AD小鼠大脑中的胆固醇代谢途径。 AD的治疗转基因小鼠改善了大脑胆固醇周转，但不影响大脑磷脂水平。而且，我们发现 DA1 治疗可稳定降低神经元细胞中的胆固醇负担和氧化应激表达APP wt或突变体。这些发现强调 ATAD3A 寡聚化是一种先前未鉴定的 AD 中脑胆固醇紊乱和神经变性的机制。我们的中心假设是 ATAD3A 寡聚化介导淀粉样蛋白病理学，通过损伤脑胆固醇代谢。该应用程序的总体目标是了解 ATAD3A 异常寡聚化介导的 AD 神经病理学，并揭示 AD 的新治疗靶点。在目标 1 中，我们将确定 ATAD3A 寡聚化对脑胆固醇稳态、AD 病理学和 AD小鼠的行为缺陷。在目标 2 中，我们将确定 AD 小鼠中 ATAD3A 是否单倍充足恢复大脑胆固醇稳态并减少 AD 病理。在目标 3 中，我们将剖析其机制 ADAD 中 ATAD3A 寡聚化与脑胆固醇稳态紊乱之间的联系。