Cardiolipin Remodeling in Alzheimer’s Disease

衰老导致大脑中的生物能量功能障碍，这与其发病机制有关 阿尔茨海默病(AD)。心磷脂(CL)是一种线粒体标志性磷脂 对于膜结构、生物能量学和信号通路来说是必不可少的。脑化学发光的改变 含量和酰基组成与神经退行性疾病的发病机制有关， 包括AD和帕金森氏病(PD)，但这些缺陷的根本原因仍然 难以捉摸。在这里，我们建议研究一种新的代谢途径，通过这种途径 CL重塑促进AD的发生发展。该途径是由ALCAT1介导的 酶，我们先前发现的第一个依赖于酰基辅酶A的溶心磷脂酰基转移酶。 我们在该领域的开创性工作已确定ALCAT1是线粒体的关键介体 与年龄相关的代谢性疾病的功能障碍。我们发现ALCAT1的表达上调 由衰老产生的活性氧通过以下途径促进线粒体功能障碍 用长链多不饱和脂肪酸催化CL的病理重塑 二十二碳六烯酸(DHA)。富含DHA使CL对氧化高度敏感 ROS损伤，导致CL过氧化和线粒体功能障碍。我们进一步表明， 消融或药物抑制ALCAT1成功地缓解了各种年龄相关的疾病 代谢性疾病。值得注意的是，我们的初步研究也确定了ALCAT1的关键作用 在将衰老与阿尔茨海默病的发展联系起来方面，我们的发现支持这一点：1)ALCAT1 缺乏显著延长小鼠的寿命；2)去除ALCAT1可恢复认知功能 并减轻AD小鼠模型中β鼠疫的形成；以及3)ALCAT1缺乏可减弱 对Aβ蛋白聚集的神经炎症反应。这些令人兴奋的发现引导我们测试 假设ALCAT1的CL重塑通过以下途径将衰老与AD的发展联系起来 促进线粒体功能障碍(图1)，这将通过三个具体目标进行测试：目标 1将确定ALCAT1的CL重塑是否将线粒体功能障碍与AD联系起来；AIM 2 将确定ALCAT1促进AD神经炎症的机制，AIM 3将 提供针对阿尔茨海默病治疗ALCAT1的概念验证研究。

Aging causes bioenergetic dysfunction in the brain, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Cardiolipin (CL) is a mitochondrial signature phospholipid that is essential for membrane structure, bioenergetics, and signaling pathways. Alterations in brain CL content and acyl compositions are implicated in the pathogenesis of neurodegenerative diseases, including AD and Parkinson’s disease (PD), but the underlying causes of these defects remain elusive. Here, we propose to investigate a novel metabolic pathway by which pathological remodeling of CL promotes the development of AD. This pathway is mediated by the ALCAT1 enzyme, the first acyl-CoA dependent lysocardiolipin acyltransferase previously identified by us. Our pioneering work in the field has identified ALCAT1 as a key mediator of mitochondrial dysfunction in age-related metabolic diseases. We show that upregulation of ALCAT1 expression by reactive oxygen species (ROS) generated by aging promotes mitochondrial dysfunction by catalyzing pathological remodeling of CL with long chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative damage by ROS, leading to CL peroxidation and mitochondrial dysfunction. We further show that ablation or pharmacological inhibition of ALCAT1 successfully mitigates various age-related metabolic diseases. Remarkably, our preliminary studies also identified a critical role of ALCAT1 in linking aging to the development of AD, which is supported by our findings that: 1) ALCAT1 deficiency significantly extends lifespan in mice; 2) Ablation of ALCAT1 restores cognitive function and mitigates Aβ plague formation in a mouse model of AD; and 3) ALCAT1 deficiency attenuates neuroinflammation in response to Aβ protein aggregation. These exciting findings lead us to test the hypothesis that CL remodeling by ALCAT1 links aging to the development of AD by promoting mitochondrial dysfunction (Fig.1), which will be tested by three Specific Aims: AIM 1 will determine whether CL remodeling by ALCAT1 links mitochondrial dysfunction to AD; AIM 2 will identify mechanisms by which ALCAT1 promotes neuroinflammation in AD, and AIM 3 will provide proof-of-concept studies in targeting ALCAT1 for the treatment of AD.