Calpain is a calcium-activated protease and there are two ubiquitously distributed mammalian calpains, namely calpain 1 (μ-calpain and CAPN1) and calpain 2 (m-calpain and CAPN2). Calpains regulate the function of many proteins by limited proteolysis. To determine the nature of different subtypes of calpain on degradation of microtubule-associated protein tau, the rat brain cortex extracts were incubated with 0.2 mmol/L, 1 mmol/L, 3 mmol/L and 5 mmol/L of CaCl₂ for 15 min at 37℃. The findings were that Ca²⁺ treatment at concentration 1～5 mmol/L led to significant proteolysis of tau protein and this degradation was blocked by calpain inhibitor, calpeptin. In addition, when the extracts containing 1 mmol/L CaCl₂ were treated with μ-calpain inhibitor (0.05 μmol/L of calpastatin) or m-calpain inhibitor (100 μmol/L calpain inhibitor Ⅳ) or both, the Ca²⁺-induced degradation of tau protein was decreased to 8.6%，92.5% and 97.8%, respectively. These data suggest that both μ-calpain and m-calpain in brain cortex extracts are activated by Ca²⁺ and both of them degrade tau protein, although, m-calpain plays a more important role in proteolysis of tau.