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REGULATION OF MITOCHONDRIAL QUALITY THROUGH MITOPHAGY IN ALZHEIMER'S DISEASE

阿尔茨海默病中通过线粒体自噬调节线粒体质量

基本信息

批准号：
10183338
负责人：
Qian Cai
金额：
$ 52.5万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183338
关键词：
Address Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Autophagocytosis Autophagosome Axonal Transport Bioenergetics Cell physiology Cessation of life Clinical Communication Data Defect Development Disease Early Intervention Energy Metabolism Event Family Functional disorder Generations Glycolysis Goals Health Homeostasis Human Image Impaired cognition Impairment Individual Intervention Life Link Lysosomes Mediating Metabolic Metabolic dysfunction Metabolism Mitochondria Mitochondrial Diseases Molecular Mus Nature Neurodegenerative Disorders Neurons Oxidative Phosphorylation Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Peptide Hydrolases Pharmacology Physiological Play Positioning Attribute Presynaptic Terminals Preventive Process Production Quality Control Reaction Reactive Oxygen Species Regulation Research Role SNAPIN gene Signal Transduction Stress Synapses Testing Therapeutic Work age related neurodegeneration aged aging population base design high risk human very old age (85+)in vivo insight mitochondrial metabolism mouse model neuronal cell body novel parkin gene/protein synaptic failure therapy design

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) affects 50% of individuals over 85 years old, and the broad impact of AD is devastating the aging population and their families—a health problem that is likely best addressed with early intervention strategies. The earliest features of the highly prevalent AD have been linked to mitochondrial abnormalities, including reduced energy production, reactive oxygen species generation, hypometabolism, and altered mitochondrial dynamics and transport. Data support that AD patients display early bioenergetic and metabolic disruptions prior to the emergence of any histopathological or clinical features. Thus, mitochondrial deficits are likely early and critical for the onset and development of AD pathology. Mitochondrial quality control, then, emerges as a central problem in AD and is a clear target point for early interference in disease. How do neurons maintain high quality mitochondria? Mitophagy, a cargo-specific autophagy, constitutes a key pathway of mitochondrial quality control that involves sequestration of aged or damaged mitochondria into autophagosomes and subsequent degradation within lysosomes. We provided the first neuronal imaging evidence showing unique features of Parkin-mediated mitophagy in live neurons. Our work further revealed that Parkin-mediated mitophagy is robustly activated at early AD disease stages, but impaired clearance of defective mitochondria is a result of lysosomal protease deficiency, which blocks degradation. Mitochondria critical for neuronal communication are situated at the synapse. The disturbance of synaptic mitochondria is a proposed early pathological event in AD. A distinctive feature of AD is the synaptic accumulation of mitophagosomes—autophagosomes containing mitochondria. Since Parkin-mediated mitophagy mainly occurs in the soma of neurons, the gap in our understanding of how the quality of synaptic mitochondria is controlled, and whether synaptic mitochondrial deficits are attributed to mitophagy dysregulation to trigger early synaptic failure in AD, must be addressed. Mitophagy controls mitochondrial quality and quantity, and was recently proposed as an important mechanism regulating energy metabolism. A long-standing question on the nature of the intersection of mitophagy and mitochondrial energetic activity in neurons remains to be addressed. Our project is designed to: 1) establish a causative link between mitophagy deficits and early synaptic pathology in a physiological AD model; 2) define mechanistic details of a strategy that can rescue mitophagy deficiency and bioenergetic dysfunction in AD mice. Our studies will advance understanding of a critical early step in AD pathogenesis. As such, our findings may provide new molecular and pharmacological targets for treating AD and normal cognitive decline.

项目总结