Letters to Nature

Nature 405, 360-364 (18 May 2000) | doi:10.1038/35012636; Received 16 December 1999; Accepted 7 April 2000

Neurotoxicity induces cleavage of p35 to p25 by calpain

Ming-sum Lee1,2, Young T. Kwon1,2, Mingwei Li3, Junmin Peng2, Robert M. Friedlander3 & Li-Huei Tsai2

  1. Howard Hughes Medical Institute and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
  2. Neuroapoptosis Laboratory, Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  3. These authors contributed equally to this work

Correspondence to: Correspondence and requests for materials should be addressed to L.-H.T. (e-mail: Email: li-huei_tsai@hms.harvard.edu).

Cyclin-dependent kinase 5 (cdk5) and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination1, 2, 3. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease4. Conversion of p35 to p25 causes prolonged activation and mislocalization of cdk5. Consequently, the p25/cdk5 kinase hyperphosphorylates tau, disrupts the cytoskeleton and promotes the death (apoptosis) of primary neurons. Here we describe the mechanism of conversion of p35 to p25. In cultured primary cortical neurons, excitotoxins, hypoxic stress and calcium influx induce the production of p25. In fresh brain lysates, addition of calcium can stimulate cleavage of p35 to p25. Specific inhibitors of calpain, a calcium-dependent cysteine protease, effectively inhibit the calcium-induced cleavage of p35. In vitro, calpain directly cleaves p35 to release a fragment with relative molecular mass 25,000. The sequence of the calpain cleavage product corresponds precisely to that of p25. Application of the amyloid beta-peptide Abeta(1–42) induces the conversion of p35 to p25 in primary cortical neurons. Furthermore, inhibition of cdk5 or calpain activity reduces cell death in Abeta-treated cortical neurons. These observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease.