Project SummaryAlzheimer's disease (AD) is the most common dementia in the elderly characterized by neurofibrillary tanglessenile plaques and a progressive loss of brain neurons. Compared with senile plaques neurofibrillary tangleshave a better correlation with the severity of cognitive impairment in AD. As intracellular lesions neurofibrillaryare largely composed of hyperphosphorylated microtubule-associated protein tau. Not surprisingly considerableefforts have been devoted to tau-based AD drug development though the pathomechanism underlying tautoxicity remains largely unknown. Mitochondrial dysfunction and neuroinflammation are prominent earlypathological features of AD and have been increasingly implicated as critical factors for AD pathogenesis.Despite both mitochondrial dysfunction and neuroinflammation have been repeatedly reported in animal modelsof tauopathies there is limited study of their interplay. Interestingly in our preliminary studies we found thatMfn2 the mitochondrial outer membrane protein regulating mitochondrial morphology and association withendoplasmic reticulum was significantly reduced in the widely used PS19 tau transgenic mice for AD and relatedtauopathies. Excitingly the overexpression of Mfn2 in neurons is sufficient to remarkably suppress tauphosphorylation mitochondrial dysfunction neuroinflammation neuronal loss and behavioral deficits in PS19mice. In addition lipopolysaccharide-induced neuroinflammation and even sudden death could also be greatlysuppressed by overexpressing Mfn2 in neurons together implying neuronal Mfn2 as a crucial mediator for bothmitochondrial dysfunction and neuroinflammation. These exciting and promising preliminary studies suggest thata detailed investigation into the potential role of Mfn2 as a point of convergence for mitochondrial dysfunctionand neuroinflammation in AD and related tauopathies is warranted. Using novel transgenic mouse models anda promising synthetic therapeutic peptide inhibiting Mfn2 degradation this study will not only study whether andhow Mfn2 regulates mitochondrial dysfunction and neuroinflammation but also test the feasibility of targetingMfn2 as a novel therapeutic approach against tau toxicity. Tau pathology is a prominent commonhistopathological feature of various major neurodegenerative diseases including but not limited to AD. Ourproposed studies of Mfn2 and its convergent role in mitochondrial dysfunction and neuroinflammation will havevery broad scientific and translational significance.