Cyclin-dependent kinase 5 (cdk5), a multi-functional kinase, and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease. Conversion of p35 to p25 causes prolonged activation and mislocalization of cdk5 and the hyperphosphorylates tau, leading to the formation of paired helical filaments and promotes apoptosis. 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 calpain1, effectively inhibit the calcium-induced cleavage of p35. In vitro, calpain1 directly cleaves p35 to release a fragment with relative molecular mass 25,000. Application of the amyloid beta-peptide A beta induces the conversion of p35 to p25 in primary cortical neurons. Inhibition of cdk5 or calpain activity reduces cell death in A beta-treated cortical neurons. These observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease. GSK3B also phosphoryklates tau but does not induce hyperphosphorylation in response to calpain activating stimuli. Additionally down-regulation or inhibition of PP2A increases the hyper-phosphorylation of tau.
7.0: Changed members. Upgraded to final version of Biocarta.
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MSigDB gene sets derived from BioCarta pathways are protected by copyright, (c) 2000-2017 BioCarta, all rights reserved. They are provided
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derived gene sets are in the MSigDB C2 and M2 collections, and can be recognized by the "BIOCARTA_" prefix in their name.
