Inhibition of calpain protects against tauopathy in transgenic P301S tau mice

Mengyu Liu, Luwen Wang, Ju Gao, Qing Dong, George Perry, Xuemei Ma, Xinglong Wang, Jesus Avila

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1077-1087
Number of pages11
JournalJournal of Alzheimer's Disease
Issue number4
StatePublished - 2019
Externally publishedYes


  • Calpain
  • Calpastatin
  • Cognitive deficits
  • Dementia
  • Motor dysfunction
  • Neurodegeneration
  • Neuroinflammation
  • Neuromuscular junction
  • Tau phosphorylation
  • Tauopathy

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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