The cysteine protease calpain cleaves the cdk5 regulator p35, releasing a 25KD fragment that accumulates in the brains of people with Alzheimer’s disease. What’s more, Aβ42 is among the factors that trigger this reaction, report Li-Huei Tsai of Harvard Medical School and her coworkers in the May 18 Nature. These findings follow on the heels of Tsai’s recent study, which established p25’s role in tau hyperphosphorylation, cytoskeletal disruption, and apoptosis of cortical neurons (see news story below, 8 December, 1999). That study raised the question which conditions foster the fateful cleavage of p35 and which enzyme carries it out.
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 Strobe
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- 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. PubMed.