Mitochondria modulate Tau pathology and neuroinflammation

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Project Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease (AD)- affected brain. Microtubule associated protein tau (MAPT) plays a major role in AD and have deleterious effects on mitochondrial and synaptic function. Accumulation of abnormal Tau, including Tau oligomers, causes mitochondrial and synaptic damage, inflammation, and memory impairment. The underlying mechanisms of abnormal Tau accumulation and strategies to eliminate them to restore mitochondrial function remain largely unknown. Cyclophilin D (CypD) is an integral part in the formation of the mitochondrial permeability transition pore (mPTP), leading to cell death. Loss of CypD protects against Aβ-induced mitochondrial and synaptic injury. However, the role of CypD in tau-mediated mitochondrial and Tau pathology has not been explored. In our preliminary studies, we found that CypD specifically interacts with tau in AD brains and Tauopathy model. Loss of CypD robustly reduced hyperphosphorylated Tau and Tau oligomers and restored mitochondrial and cognitive function in human mutant Tau mice. Furthermore, CypD-deficient Tau mice revealed suppression of induction of proinflammatory mediators. These exciting results lead us to hypothesize that CypD-mediated mitochondrial dysfunction provokes neuroinflammation, contributing to abnormal tau metabolism and clearance. To test this hypothesis, we will investigate whether blockade of CypD promotes abnormal tau clearance consequently reducing tauopathy and thereby alleviating tau-induced aberrant mitochondrial and cognitive decline in AD. Utilizing novel genetically manipulated CypD-AD mouse models and neuronal culture with altered CypD levels in tau-rich environment, and AD cybrids containing patient AD-derived mitochondria, we will elucidate CypD- dependent mechanisms underlying Tau pathology, clearance, mitochondrial alterations, and neuroinflammation.