Cardiolipin Remodeling in Alzheimer’s Disease

阿尔茨海默病中的心磷脂重塑

基本信息

批准号：
10645569
负责人：
YUGUANG SHI
金额：
$ 33.91万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645569
关键词：
APP-PS1 Ablation Acyl Coenzyme A Acyltransferase Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid beta-Protein Attenuated Bioenergetics Brain Cardiolipins Cells Cognitive deficits Data Defect Development Docosahexaenoic Acids Enzymes Functional disorder Generations Genes Goals Heart failure Impairment Inflammasome Knock-in Mouse Link Longevity Mediating Mediator Membrane Metabolic Metabolic Diseases Metabolic Pathway Microglia Mitochondria Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Oxidative Phosphorylation Oxidative Stress Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Phospholipids Plague Polyunsaturated Fatty Acids Production Reactive Oxygen Species Risk Factors Role Senile Plaques Signal Pathway Tauopathies Testing Up-Regulation Work abeta accumulation age related cognitive function effective therapy inhibitor lipidomics mitochondrial dysfunction mouse model neuroinflammation new therapeutic target novel oxidative damage peroxidation pharmacologic prevent protein aggregation response targeted treatment tau Proteins

项目摘要

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.

衰老导致大脑生物能功能障碍，这与发病机制有关心磷脂 (CL) 是一种线粒体特征磷脂。对于大脑 CL 的膜结构、生物能量学和信号通路的改变至关重要。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 和帕金森病 (PD)，但这些缺陷的根本原因仍然存在在这里，我们建议研究一种新的代谢途径，通过该途径来实现病理学。 CL 的重塑促进 AD 的发展。该途径由 ALCAT1 介导。酶，我们之前发现的第一个酰基辅酶A依赖性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 是线粒体的关键介质我们发现 ALCAT1 表达上调。衰老产生的活性氧 (ROS) 会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，例如二十二碳六烯酸 (DHA) 的富集使 CL 对氧化高度敏感。 ROS，导致 CL 过氧化损伤和线粒体功能障碍。 ALCAT1 的消融或药物抑制成功减轻了各种与年龄相关的症状值得注意的是，我们的初步研究还确定了 ALCAT1 的关键作用。将衰老与 AD 的发展联系起来，我们的研究结果支持了这一点：1) ALCAT1 2) 去除ALCAT1可恢复认知功能并减轻 AD 小鼠模型中 Aβ 鼠疫的形成；3) ALCAT1 缺陷减弱；这些令人兴奋的发现促使我们进行测试。 ALCAT1 的 CL 重塑将衰老与 AD 的发展联系起来的假设促进线粒体功能障碍（图1），将通过三个具体目标进行测试：AIM 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；将确定 ALCAT1 促进 AD 神经炎症的机制，AIM 3 将提供针对 ALCAT1 治疗 AD 的概念验证研究。