Alzheimer's disease (AD) is the most common dementia in the elderly characterized by neurofibrillary tangles, senile plaques and a progressive loss of brain neurons. Compared with senile plaques, neurofibrillary tangles have a better correlation with the severity of cognitive impairment in AD. As intracellular lesions, neurofibrillary are largely composed of hyperphosphorylated microtubule-associated protein tau. Not surprisingly, considerable efforts have been devoted to tau-based AD drug development though the pathomechanism underlying tau toxicity remains largely unknown. Mitochondrial dysfunction and neuroinflammation are prominent early pathological 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 models of tauopathies, there is limited study of their interplay. Interestingly, in our preliminary studies, we found that Mfn2, the mitochondrial outer membrane protein regulating mitochondrial morphology and association with endoplasmic reticulum, was significantly reduced in the widely used PS19 tau transgenic mice for AD and related tauopathies. Excitingly, the overexpression of Mfn2 in neurons is sufficient to remarkably suppress tau phosphorylation, mitochondrial dysfunction, neuroinflammation, neuronal loss and behavioral deficits in PS19 mice. In addition, lipopolysaccharide-induced neuroinflammation and even sudden death could also be greatly suppressed by overexpressing Mfn2 in neurons, together implying neuronal Mfn2 as a crucial mediator for both mitochondrial dysfunction and neuroinflammation. These exciting and promising preliminary studies suggest that a detailed investigation into the potential role of Mfn2 as a point of convergence for mitochondrial dysfunction and neuroinflammation in AD and related tauopathies is warranted. Using novel transgenic mouse models and a promising synthetic therapeutic peptide inhibiting Mfn2 degradation, this study will not only study whether and how Mfn2 regulates mitochondrial dysfunction and neuroinflammation, but also test the feasibility of targeting Mfn2 as a novel therapeutic approach against tau toxicity. Tau pathology is a prominent common histopathological feature of various major neurodegenerative diseases including but not limited to AD. Our proposed studies of Mfn2 and its convergent role in mitochondrial dysfunction and neuroinflammation will have very broad scientific and translational significance.
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly characterized by the pathological hallmark neurofibrillary tangles. While the anti-A? strategy in AD has been disappointing, a deeper understanding of tauopathy potentially provides novel therapeutic targets for AD. Our study has identified the mitochondrial outer membrane protein Mfn2 as a likely linker between mitochondrial dysfunction and neuroinflammation in tauopathy experimental models for AD. Based on pilot studies showing the remarkable ability of Mfn2 in neurons to greatly suppress tauopathy and associated mitochondrial dysfunction, neuroinflammation and even neuronal loss, we will investigate whether Mfn2 acts as a point of convergence for mitochondrial dysfunction and neuroinflammation in tau transgenic mice, and more importantly, test whether targeting Mfn2 can be a novel therapeutic approach for the treatment of AD and related tauopathies.
