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Pink1, amyloid pathology, and mitochondrial quality control in Alzheimer's Disease

阿尔茨海默病中的 Pink1、淀粉样蛋白病理学和线粒体质量控制

基本信息

批准号：
9539108
负责人：
Shirley ShiDu Yan
金额：
$ 17.49万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
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：
2018-07-01 至 2019-05-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9539108
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Attenuated Autophagocytosis Bioenergetics Blood Platelets Brain Brain Diseases Brain Pathology Cell Line Cells Cerebrum Chronic Cognition Cognitive Data Defect Development Disease Disease Progression Down-Regulation Environment Failure Functional disorder Gene Delivery Genetic Genetic Transcription Goals Human Hybrids Impaired cognition Impairment In Vitro Injury Learning Link Maintenance Mediating Mediator of activation protein Memory Memory impairment Metabolism Mitochondria Mitochondrial Diseases Mus NF-kappa B Neurons Nuclear Outcome Oxidative Stress PTEN-induced putative kinase Pathogenesis Pathogenicity Pathologic Pathology Patients Peptide Metabolism Peripheral Phosphotransferases Preventive Intervention Proteins Quality Control Reactive Oxygen Species Regulation Research Resistance Respiration Risk Factors Role Signal Transduction Stress Synapses Synaptic plasticity Technology Therapeutic Agents Therapeutic Intervention Tissues Transgenic Mice Transgenic Organisms abeta accumulation aged amyloid pathology base human model improved insight mouse model mutant new therapeutic target novel novel therapeutics protein expression receptor repaired synaptic function

项目摘要

Mitochondrial and synaptic dysfunction is early pathological features of the Alzheimer’s disease (AD)-affected brain. Perturbed bioenergetics function, respiration failure, aberrant mitochondrial dynamics, and increased levels of reactive oxygen species (ROS) are observed in brains and peripheral tissues including platelets of subjects with AD. Amyloid-β peptide (Aβ) has deleterious effects on mitochondrial and synaptic function. The underlying mechanisms and strategies to repair such injury remain unclear. PTEN-induced putative kinase 1 (PINK1) is important for the maintenance of mitochondrial integrity and quality control by conferring resistance to oxidative stress and toxic insults, modulating proper mitochondrial dynamics, and by eliminating and removing damaged mitochondria via mitophagy. So far, the role of PINK1 in amyloid pathology and Aβ- induced mitochondrial and synaptic defects is unexplored. We hypothesize that impairment of PINK1 function contributes to chronic Aβ accumulation relevant to the development of amyloid pathology in AD and to mitochondrial and synaptic degeneration. The goal of this proposal is to gain new insights into the role of PINK1 in AD pathogenesis, focusing on Aβ accumulation/clearance, amyloid pathology, mitochondrial quality control (function, dynamics, mitochondrial clearance), and synaptic function, utilizing gene delivery of PINK1 technology, novel genetically manipulated transgenic PINK1/AD mouse models and neuronal culture with altered PINK1 levels in neurons, and human neuronal cells containing mitochondria derived from AD and normal aged-matched subjects. The outcomes of the project could present PINK1 as a potential new therapeutic target for limiting amyloid pathology and maintaining mitochondrial integrity thereby halting AD progression.

线粒体和突触功能障碍是阿尔茨海默病（AD）的早期病理特征，个脑袋生物能量学功能紊乱，呼吸衰竭，线粒体动力学异常，在脑和外周组织中观察到活性氧（ROS）水平， AD患者。淀粉样β肽（Aβ）对线粒体和突触功能具有有害作用。的修复这种损伤的潜在机制和策略仍不清楚。PTEN诱导的推定激酶1 （PINK 1）对于通过赋予抗性来维持线粒体完整性和质量控制是重要的氧化应激和毒性损伤，调节适当的线粒体动力学，并通过消除和通过线粒体自噬去除受损的线粒体。到目前为止，PINK 1在淀粉样蛋白病理学和Aβ- 诱导的线粒体和突触缺陷尚未探索。我们假设PINK 1功能受损有助于与AD中淀粉样蛋白病理学的发展相关的慢性Aβ积累，线粒体和突触变性。本提案的目的是对以下方面的作用有新的认识： PINK 1在AD发病机制中的作用，重点关注Aβ积聚/清除、淀粉样蛋白病理学、线粒体质量控制（功能，动力学，线粒体清除）和突触功能，利用PINK 1的基因递送技术，新的遗传操作的转基因PINK 1/AD小鼠模型和神经元培养，神经元和含有来源于AD的线粒体的人神经元细胞中改变的PINK 1水平，正常年龄匹配的受试者。该项目的成果可以将PINK 1作为一个潜在的新的用于限制淀粉样蛋白病变和维持线粒体完整性从而阻止AD的治疗靶点进展