A cdk5-p35 stable complex is involved in the beta-amyloid-induced deregulation of cdk5 activity in hippocampal neurons

The cdk5 and its activator p35 constitute one of the main tau-phosphorylati ng systems in neuronal cells. Under normal conditions for neurons, its acti vity is required for modulating tau involvement in neuronal polarity and in development of the mammalian central nervous system. Recently, we reported that the treatment of rat hippocampal cells in culture with fibrillary bet a -amyloid (A beta) results in deregulation of the protein kinase cdk5, The neurotoxic effects of A beta fibrils were prevented by inhibition of cdk5 activity by butyrolactone I or by using antisense oligonucleotides that con trol the expression of this kinase. Here, we show that the A beta -promoted increase of cdk5 activity is associated with changes in tan phosphorylatio n patterns and in the intraneuronal distribution of tau. In addition to hip pocampal cells, deregulation of cdk5 was observed in other cell types. Howe ver, butyrolactone I prevented A beta -induced cell death only in neuronal cells in which cdk5 activation was sensitive to A beta fibrils. This lost o f cdk5 regulation in hippocampal cells exposed to A beta fibrils appears to be associated with an increase in the cdk5-p35 complex stability. Complex stabilization was sensitive to phosphorylation of cdk5, However, no changes in cdk5 and p35 mRNAs were observed, suggesting that the main effects on c dk5 occur at the posttranslational level. These studies indicate that cdk5 phosphorylation and the formation of an abnormally active cdk5-p35 complex are directly involved in the molecular paths leading to the neurodegenerati ve process of rat hippocampal neurons triggered by A beta fibrils, (C) 2001 Academic Press.