Cdk5 is a neuronal kinase involved in synaptic plasticity and memory formation. When overactive, Cdk5 can induce cell cycle arrest, tau hyperphosphorylation and apoptosis. This dichotomy in function is correlated with the degree of Cdk5 activation by small regulators. P25 is the most potent activator of Cdk5, absent in neurons under physiological conditions but induced during neuronal insults. In mouse models, high levels of p25 lead to neurodegeneration. Consistently, aged mice with life long exposure to low p25 levels exhibit tau hyperphosphorylation. However, expression of low p25 levels can improve learning in a sex-specifi c manner in young adult mice. The underlying molecular mechanisms of this dose effect are still poorly understood. Therefore, in the project presented we have undertaken comparative proteomics on hippocampal synaptosomes from wildtype and p25 mutant mice of both sexes. Four different approaches of tandem mass tag labeling were employed. From more than 500 quantifi able proteins, we identifi ed sex-specifi c changes in the p25 transgenics compared to wildtype mice. Selected proteins will be introduced and implications for the role of Cdk5-p25 in memory and neurodegeneration will be discussed. This work was supported by an MRC PhD studentship.
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