The role of cyclin-dependent kinase 5 in Alzheimer's disease pathogenesis

Cdk5 is a proline-directed serine/threonine protein kinase that regulates the migration of neurons during development of the central nervous system. In Alzheimer's disease brains, the Cdk5 activator p35 is proteolytically cleaved into the truncated p25 form. Generation of p25 disrupts the normal regulation of Cdk5 by causing its prolonged activation and mislocalization. Deregulation of Cdk5 leads to hyperphosphorylation of tau, disruption of the cytoskeleton and neuronal cell death.; Proteolytic cleavage of p35 into p25 is mediated by the calcium-activated cysteine protease calpain. Application of the amyloid β-peptide induces the conversion of p35 to p25 in primary cortical neurons. Inhibition of Cdk5 or calpain activity reduces cell death in Aβ-treated cortical neurons, indicating that the calpain-mediated p35 to p25 conversion pathway is part of the mechanism by which Aβ causes cell death.; One of the downstream targets of Cdk5 is the amyloid precursor protein (APP). APP is phosphorylated on threonine 668 (T668) in the cytoplasmic tail. The p25/Cdk5 kinase induces T668 phosphorylation in primary neurons and in transgenic mice. In the hippocampus of AD brains, T668 phosphorylated APP is upregulated in large pyramidal neurons that, in many cases, also display hyperphosphorylated tau. In these neurons, phosphorylated APP accumulates in large vesicular structures recognized by endosome markers but not by other organelle markers. Cdk5, its activator p25, as well as active m-calpain, all colocalize with phosphorylated APP in these enlarged endosomes. Western blot analysis of brain samples reveals elevated T668 phosphorylated APP C-terminal fragments in many AD hippocampal lysates. Mass spectrometric results further indicate that APP C-terminal fragments are hyperphosphorylated on many other sites, in addition to T668, in AD brain samples. Intriguingly, pharmacological inhibition of Cdk5 activity reduces the production of Aβ peptides in neurons derived from the APP(Sw) transgenic mouse model of Alzheimer's disease. These results suggest that deregulation of Cdk5 and increased phosphorylation of APP in AD brains may have impact on APP processing and Aβ production.