PINK1 signaling and synaptic mitochondria integrity in AD

总结 线粒体功能障碍是阿尔茨海默病（Alzheimer's disease，AD）早期脑组织的病理特征。存储器 AD中的损伤是脑病理学的表现，例如淀粉样蛋白-β肽（Aβ）的积累， 线粒体损伤在AD的一生中，受损的线粒体在大脑中逐渐积累， 受影响的神经元，这可能是由于清除能力不足，以消除增加的数量 有缺陷的线粒体。因此，增加或减少的缺陷或健康的水平， AD脑中的线粒体扰乱了健康和功能障碍的线粒体之间的稳态平衡， 导致线粒体病变并导致认知功能障碍。潜在的致病因素 AD的机制和有效的疾病改善疗法仍然难以捉摸。PTEN诱导的推定激酶1 （PINK 1）对于维持线粒体完整性和质量控制很重要。到目前为止，PINK 1在 AD中的线粒体病理学和认知功能障碍仍然未被探索。我们假设 AD中PINK 1功能的损伤是线粒体变性的基础，导致认知能力下降。 利用PINK 1基因导入技术，新型转基因PINK 1/AD模型，我们将阐明PINK 1- Aβ介导的线粒体改变的依赖机制。该项目的完成将 通过靶向PINK 1以维持线粒体完整性，为治疗AD开辟了新途径。

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.