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氏病（AD）影响的早期病理特征脑。扰动的生物能功能，呼吸衰竭，异常线粒体动力学和增加在大脑和外围组织中观察到活性氧（ROS）的水平，包括血小板 AD主题。淀粉样蛋白β果皮（Aβ）对线粒体和突触功能有删除的影响。这维修这种伤害的基本机制和策略尚不清楚。 PTEN诱导的假定激酶1 （Pink1）对于通过会议阻力来维持线粒体完整性和质量控制很重要氧化物胁迫和有毒感染，调节适当的线粒体动力学，并消除和消除和通过线粒体去除损坏的线粒体。到目前为止，Pink1在淀粉样病理学和Aβ-中的作用诱导的线粒体和突触缺陷是出乎意料的。我们假设PINK1功能的损害有助于与AD中淀粉样蛋白病理学发展相关的慢性Aβ积累线粒体和突触变性。该提案的目的是获得有关对角色作用的新见解 PINK1在AD发病机理中，重点是Aβ积累/清除率，淀粉样病理学，线粒体质量使用pink1的基因递送控制（功能，动力学，线粒体清除率）和突触功能技术，新型遗传操纵的转基因PINK1/AD小鼠模型和神经元文化神经元中的PINK1水平改变了，以及含有AD和的线粒体的人神经元细胞正常年龄匹配的受试者。该项目的结果可能会呈现为PINK1作为潜在的新限制淀粉样病理学和维持线粒体完整性的治疗靶点，从而停止AD 进展。