Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline

Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer's disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.