Role of brain lipid metabolism in Alzheimer's disease

环境和遗传因素都参与了胆固醇代谢的紊乱。 被认为是阿尔茨海默病(AD)发展的危险因素。胆固醇的积累有 在阿尔茨海默病患者和动物的受累脑区观察到，它与区域特异性有关 突触丢失。脑胆固醇升高会导致认知障碍、淀粉样蛋白β(Aβ)的产生和 聚集和tau病理。尽管有这些观察，控制大脑胆固醇的机制 AD相关病理条件下的动态平衡和对神经元的影响仍然难以捉摸。特别是， 该领域缺乏对神经元胆固醇信号通路所涉及的因素的了解。 代谢，与AD病理的发生和发展有关。ATAD3A属于一个新的家族 真核细胞线粒体AAA-ATPase。ATAD3A通过调节胆固醇的稳态和运输 线粒体相关内质网膜(MAM)是MAM的一个特殊亚域，其机制尚不清楚。 它具有脂筏的特征，富含胆固醇和神经鞘蛋白。我们最近的工作 证明ATAD3A通过病理性二聚化表现出一种功能增强，从而导致 亨廷顿病的神经退行性变。我们进一步观察到ATAD3A寡聚的增强 在AD神经元培养中，在AD转基因小鼠脑中和在AD患者死后海马区中， 提示ATAD3A活性异常在AD发病机制中起重要作用。我们开发了一种新型的多肽抑制剂 与ATAD3A结合以阻断ATAD3A二聚的DA1。值得注意的是，DA1的持续治疗减少了 5XFAD的APP水平和淀粉样蛋白负荷、减轻神经炎症和改善短期空间记忆 转基因小鼠。此外，我们的蛋白质组学分析表明，通过DA1阻断ATAD3A寡聚 治疗主要影响AD小鼠脑内胆固醇代谢途径。阿尔茨海默病的治疗 转基因小鼠改善了大脑胆固醇的转化，但不影响大脑磷脂水平。此外， 我们发现DA1治疗稳定地降低了神经细胞的胆固醇负荷和氧化应激。 表达APP wt或突变体。这些发现突显了ATAD3A齐聚是一种以前未确定的 阿尔茨海默病脑胆固醇紊乱和神经退行性变的机制。我们的中心假设是 ATAD3A寡聚介导淀粉样蛋白病理，导致神经退行性变，通过损害 大脑胆固醇代谢。本应用程序的总体目标是了解ATAD3A异常 寡聚介导AD的神经病理学，并揭示AD的新的治疗靶点。在目标1中，我们 将确定ATAD3A寡聚对脑胆固醇稳态、AD病理和 阿尔茨海默病小鼠行为缺陷。在目标2中，我们将确定ATAD3A在AD小鼠中的单效 恢复脑内胆固醇平衡，减少AD的病理改变。在目标3中，我们将剖析机械论 ATAD3A寡聚与阿尔茨海默病患者脑内胆固醇稳态紊乱之间的联系。

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.