The present report answers these questions. Collaborating with Robert Friedlander, also of Harvard Medical School, Tsai first discovered that transient focal ischemia in mice induced p25 in the same side of the brain. (P25 has never been detected in healthy brain.) Then her group showed that free radicals, glutamate, and elevated intracellular calcium stimulate the conversion of p35 into p25 in cultured primary neurons. Inhibitors of the calcium-dependent protease calpain inhibited this reaction. Moreover, calpain cleaved p35 in brain lysates and, when assayed with purified p35, it generated a cleavage product whose sequence was identical to that of p25. Finally, the researchers found that Aβ42 leads to the generation of p25, and that calpain inhibitors rescued Aβ-induced neuronal death of cultured neurons.

Calpain has long been suspected to play a role in neurotoxicity. Randy Nixon, now at New York University, reported in 1997 that its activated form accumulated in neurofibrillary tangles, as well as pre-tangle structures, in neurons of people with AD.

Given that agents of neurotoxicity-glutamate overexcitation, hypoxic stress, and Aβ peptides-converge to alter calcium homeostasis in affected neurons, Tsai suggests that calpain’s conversion of p35 into p25 represents one mechanism by which these agents can lead to hyperphosphorylation of tau and cell death, thus contributing to Alzheimer’s pathology. This mechanism represents an example for how cdk5-a kinase essential to proper brain development and adult function-can be corrupted into damaging neurons, the authors write.-Gabrielle Strobel.

Reference:Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH. Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 2000 May 18;405(6784):360-4. Abstract