REGULATION OF MITOCHONDRIAL QUALITY THROUGH MITOPHAGY IN ALZHEIMER'S DISEASE

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.