PINK1 signaling and synaptic mitochondria integrity in AD

AD 中的 PINK1 信号传导和突触线粒体完整性

基本信息

批准号：
10091121
负责人：
SHI FANG YAN
金额：
$ 22.73万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091121
关键词：
PINK1 signaling synaptic mitochondria integrity

项目摘要

Summary Mitochondrial dysfunction is the early pathological feature of Alzheimer’s disease (AD)-affected brain. Memory impairment in AD is a manifestation of brain pathologies such as accumulation of amyloid-β peptide (Aβ) and mitochondrial damage. Damaged mitochondria are progressively accumulated in brain over the lifetime of AD- affected neurons, which is likely attributable to inadequate clearance capacity in removing increased numbers of defective mitochondria from nerve cells. Therefore, increased or decreased levels of defective or healthy mitochondria in AD brains disturb the homeostatic balance between healthy and dysfunctional mitochondria, leading to mitochondrial pathology and contributing to cognitive dysfunction. The underlying pathogenic mechanisms and effective disease modifying therapies for AD remain elusive. PTEN-induced putative kinase 1 (PINK1) is important for maintaining mitochondrial integrity and quality control. So far, the role of PINK1 in mitochondrial pathology and cognitive dysfunction in AD remains unexplored. We hypothesize that the impairment of PINK1 function in AD underlies mitochondrial degeneration, leading to cognitive decline. Utilizing gene delivery of PINK1 technology, novel transgenic PINK1/AD models, we will elucidate PINK1- dependent mechanisms underlying Aβ-mediated mitochondrial alterations. The completion of this project will open up a new avenue for the treatment of AD by targeting PINK1 to maintain mitochondrial integrity.

概括线粒体功能障碍是阿尔茨海默病（AD）影响的大脑的早期病理特征。 AD 的损伤是大脑病理学的表现，例如淀粉样蛋白-β 肽 (Aβ) 的积累和线粒体损伤在 AD 患者的一生中逐渐在大脑中积累。受影响的神经元，这可能是由于清除数量增加的清除能力不足因此，有缺陷或健康的线粒体水平增加或减少。 AD大脑中的线粒体扰乱了健康线粒体和功能失调线粒体之间的稳态平衡，导致线粒体病理并导致认知功能障碍。 PTEN 诱导的推定激酶 1 的机制和有效的疾病缓解疗法仍然难以捉摸。 (PINK1) 对于维持线粒体完整性和质量控制很重要到目前为止，PINK1 在以下方面的作用。 AD 中的线粒体病理学和认知功能障碍仍有待探索。 AD 中 PINK1 功能受损是线粒体变性的基础，从而导致认知能力下降。利用 PINK1 技术的基因传递，新型转基因 PINK1/AD 模型，我们将阐明 PINK1- Aβ 介导的线粒体改变的依赖机制。通过靶向 PINK1 维持线粒体完整性，为 AD 治疗开辟了新途径。