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Mitochondria modulate Tau pathology and neuroinflammation

线粒体调节 Tau 病理学和神经炎症

基本信息

批准号：
10263269
负责人：
Shirley ShiDu Yan
金额：
$ 59.59万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10263269
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Attenuated Behavioral Blood Platelets Brain Cell Death Cell Line Cell Membrane Permeability Cerebrum Cognitive Data Defect Disease Progression Environment Functional disorder Genetic Goals Human Hybrids Immune Impaired cognition In Vitro Inflammation Inflammatory Injury Lead Learning Link MAPT gene Maintenance Mediating Mediator of activation protein Memory Memory impairment Metabolism Microglia Mitochondria Mitochondrial DNA Mitochondrial Diseases Modeling Molecular Mus Natural Immunity Nerve Degeneration Neurons Outcome Outcome Study Pathogenesis Pathologic Pathology Patients Pattern Pattern recognition receptor Peptidylprolyl Isomerase Phagocytosis Play Production Property Research Role Signal Transduction Stress Structure Synapses Synaptic Transmission Synaptosomes TLR9 gene Tauopathies Testing Therapeutic Agents Toxic effect Transcriptional Activation chemokine cognitive function cyclophilin D cytokine feasibility research genetic manipulation human model hyperphosphorylated tau in vivo insight mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore mouse model neurofibrillary tangle formation neuroinflammation neuron loss new therapeutic target novel novel therapeutics protective effect receptor for advanced glycation endproducts response synaptic function synaptic pruning tau Proteins tau aggregation tau mutation tau-1 transcription factor

项目摘要

Project Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease (AD)- affected brain. Microtubule associated protein tau (MAPT) plays a major role in AD and have deleterious effects on mitochondrial and synaptic function. Accumulation of abnormal Tau, including Tau oligomers, causes mitochondrial and synaptic damage, inflammation, and memory impairment. The underlying mechanisms of abnormal Tau accumulation and strategies to eliminate them to restore mitochondrial function remain largely unknown. Cyclophilin D (CypD) is an integral part in the formation of the mitochondrial permeability transition pore (mPTP), leading to cell death. Loss of CypD protects against Aβ-induced mitochondrial and synaptic injury. However, the role of CypD in tau-mediated mitochondrial and Tau pathology has not been explored. In our preliminary studies, we found that CypD specifically interacts with tau in AD brains and Tauopathy model. Loss of CypD robustly reduced hyperphosphorylated Tau and Tau oligomers and restored mitochondrial and cognitive function in human mutant Tau mice. Furthermore, CypD-deficient Tau mice revealed suppression of induction of proinflammatory mediators. These exciting results lead us to hypothesize that CypD-mediated mitochondrial dysfunction provokes neuroinflammation, contributing to abnormal tau metabolism and clearance. To test this hypothesis, we will investigate whether blockade of CypD promotes abnormal tau clearance consequently reducing tauopathy and thereby alleviating tau-induced aberrant mitochondrial and cognitive decline in AD. Utilizing novel genetically manipulated CypD-AD mouse models and neuronal culture with altered CypD levels in tau-rich environment, and AD cybrids containing patient AD-derived mitochondria, we will elucidate CypD- dependent mechanisms underlying Tau pathology, clearance, mitochondrial alterations, and neuroinflammation.

项目概要线粒体功能障碍和突触损伤是阿尔茨海默病（AD）的早期病理特征—— 受影响的大脑。微管相关蛋白 tau (MAPT) 在 AD 中起主要作用并具有有害作用关于线粒体和突触功能。异常 Tau（包括 Tau 寡聚体）的积累会导致线粒体和突触损伤、炎症和记忆障碍。其基本机制异常 Tau 积累和消除它们以恢复线粒体功能的策略仍然存在很大问题未知。亲环蛋白 D (CypD) 是线粒体通透性转变形成中不可或缺的一部分孔（mPTP），导致细胞死亡。 CypD 的缺失可以防止 Aβ 诱导的线粒体和突触损伤。然而，CypD 在 tau 介导的线粒体和 Tau 病理学中的作用尚未被探索。在我们的初步研究，我们发现 CypD 在 AD 大脑和 Tau 病模型中与 tau 特异性相互作用。损失 CypD 显着减少了过度磷酸化的 Tau 和 Tau 寡聚体，并恢复了线粒体和认知能力在人类 Tau 突变小鼠中发挥作用。此外，CypD 缺陷的 Tau 小鼠显示出对诱导的抑制促炎介质。这些令人兴奋的结果使我们推测 CypD 介导的线粒体功能障碍会引发神经炎症，导致 tau 代谢和清除异常。为了测试这个假设，我们将研究 CypD 的阻断是否会因此促进异常的 tau 清除减少 tau 蛋白病，从而缓解 AD 中 tau 蛋白引起的异常线粒体和认知能力下降。利用新型基因操纵 CypD-AD 小鼠模型和改变 CypD 水平的神经元培养物在富含 tau 的环境中，以及含有患者 AD 衍生线粒体的 AD cybrids，我们将阐明 CypD- Tau 病理学、清除、线粒体改变和神经炎症的依赖机制。