PINK1 signaling and synaptic mitochondria integrity in AD

摘要 线粒体功能障碍是阿尔茨海默病(AD)脑损害的早期病理特征。记忆 阿尔茨海默病的损害是大脑病理的一种表现，如淀粉样蛋白β肽(Aβ)和 线粒体受损。受损的线粒体在阿尔茨海默病患者的一生中逐渐积累在大脑中- 受影响的神经元，可能是由于清除数量增加的清除能力不足所致 神经细胞中有缺陷的线粒体。因此，缺陷或健康的水平增加或减少 AD大脑中的线粒体扰乱了健康和功能失调的线粒体之间的动态平衡， 导致线粒体病变并导致认知功能障碍。潜在的致病因素 阿尔茨海默病的机制和有效的疾病修正疗法仍然难以捉摸。PTEN诱导的可能的蛋白激酶1 (PINK1)对于维持线粒体的完整性和质量控制是重要的。到目前为止，PINK1在 阿尔茨海默病的线粒体病理和认知功能障碍仍未被研究。我们假设 阿尔茨海默病患者PINK1功能受损是线粒体变性的基础，导致认知功能下降。 利用PINK1基因传递技术，建立新型的转基因PINK1/AD模型，我们将阐明PINK1- Aβ介导的线粒体改变的依赖机制。这项工程的竣工将 通过靶向PINK1来维持线粒体的完整性，为AD的治疗开辟了一条新的途径。

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.