Sci. STKE, 23 May 2000
Neurobiology Calpain Cleaves p35-Implications for Alzheimer's Disease
Accumulation of the amyloid beta peptide Aβ(1-42) into plaques within neurons correlates highly with ensuing neuronal apoptosis. Concomitant proteolytic cleavage of the brain-specific activator protein of Cdk5, termed p35, into p25 is observed in amyloid-containing apoptotic neurons of patients with Alzheimer's disease. Cleavage of p35 to p25 leads to the constitutive activation and mislocalization of Cdk5. Lee et al. undertook experiments to determine the conditions and enzymes responsible for cleaving p35. Surgically induced ischemia in murine brain arteries led to the production of p25 in cortical tissue, and cultured primary neurons produced p25 when treated with H2O2, high levels of glutamate, or ionomycin. Cleavage of p35 was Ca2+-dependent, as chelating agents blocked the endogenous proteolytic activity. Similarly, only the addition of Ca2+ but not other divalent or monovalent cations to murine brain lysates led to the appearance of p25. Calpain-specific inhibitors blocked p35 cleavage, and immunodepletion experiments revealed that calpain was responsible for p35 cleavage in vitro. Treatment of cultured primary neurons with Aβ(1-42) led to the conversion of p35 to p25, presumably through the formation of neurotoxic amyloid plaques. Thus, because Aβ(1-42) can elicit the production of p25 and the subsequent constitutive activation and redirected localization of Cdk5, and because redirected Cdk5 phosphorylates the microtubule-associated protein, Tau, leading to cytoskeletal disruption and neuronal apoptosis, this suggests a mechanism for the molecular pathogenesis of Alzheimer's disease.
Lee, M.-S., Kwon, Y.T., Li, M., Peng, J., Friedlander, R.M., and Tsai, L.-H. (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405: 360-364. [Online Journal]
Citation: Calpain Cleaves p35-Implications for Alzheimer's Disease. Sci. STKE 2000, tw1 (2000).
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