Alzheimer＇s　disease　(AD)　and　other　tauopathies　are　characterized　by　intracellular　accumulation　of　microtubuleassociated　tau　protein　leading　to　neurodegeneration.　Calpastatin　is　the　endogenous　inhibitor　of　calpain,　a　calcium-dependent　cysteine　protease　that　has　been　increasingly　implicated　in　tauopathies.　In　this　study,　we　generated　a　neuron　specific　calpastatin　overexpressing　knock-in　transgenic　mouse　model　and　crossed　it　with　the　PS19　tauopathy　mouse　model　expressing　human　P301S　mutant　tau　protein.　The　forced　expression　of　calpastatin　in　neurons　significantly　alleviated　tau　hyperphosphorylation　measured　by　immunocytochemistry　and　immunoblot.　The　genetic　inhibition　of　calpain　by　calpastatin　also　greatly　suppressed　characteristic　hippocampal　neuron　loss　and　widespread　astrogliosis　and　microgliosis　in　PS19　mice.　Consistently,　PS19　mice　with　neuronal　calpastatin　overexpression　exhibited　remarkably　alleviated　cognitive　deficits,　muscle　weakness,　skeletal　muscle　atrophy,　and　neuromuscular　denervation,　together　implying　the　neuroprotective　effects　of　neuronal　calpastatin　in　PS19　mice　of　tauopathy.　In　sum,　this　study　provides　additional　evidence　supporting　the　pathological　role　of　calpain　in　neurodegenerative　diseases　associated　with　tau　pathology,　and　suggests　that　targeting　calpain　is　likely　a　promising　therapeutic　approach　for　these　devastating　diseases.