Summary: Microtubule associated protein tau (MAPT) plays a major role in Alzheimer’s disease (AD) and related disorder (ADRD) and have deleterious effects on mitochondrial and synaptic function and neuroinflammation. Tau oligomers, prior to neurofibrillary tangle (NFT) formation, are toxic species responsible for tau toxicity, mitochondrial and synaptic damage, and memory impairment. However, the underlying mechanisms of abnormal tau accumulation and strategies to eliminate them remain largely unknown. There is limited mechanistic study investigating the likely interplays between mitochondrial dysfunction and neuroinflammation and their contribution to synaptic damage and tauopathy in AD and related disorder (ADRD). PTEN-induced putative kinase 1 (PINK1) is important for the maintenance of mitochondrial integrity and quality control via mitophgy. PINK1 was significantly decreased in AD-affected brains, AD mice, including widely used tauopathy mice, suggesting defective mitophagy in AD and ADRD. Development and validation of biological activity of PINK1 enhancer remains to be explored. This proposal will address the fundamental unexplored questions of whether PINK1 is a key player in tau-related aberrant mitochondria and synaptic injury and mitochondria-mediated neuroinflammation and whether genetic and pharmacological enhancement of PINK1 proves beneficial for tau clearance, mitochondrial quality control, and cognitive function as a potential therapeutic strategy in AD and ADRD. We will elucidate PINK1-dependent new mechanisms underlying tau pathology and clearance, proper mitochondrial and synaptic function via PINK1/mitochondria/neuroinflammation axis relevant to the pathogenesis of neurodegeneration by employing PINK1 novel genetically manipulated transgenic mouse models and pharmacological PINK1 enhancer in tau-rich environment, and human neuronal cells containing patient AD- and non-AD-derived mitochondria.