CDK5 is a proline-directed serine/threonine kinase essential for neuronal development and function, activated uniquely by non-cyclin proteins p35 and p39 rather than classical cyclins 1. However, CDK5 also partners with cyclin B1 to maintain mitotic fidelity in dividing cells 2. In neurons, CDK5 regulates survival, migration, differentiation, axonal growth, synaptogenesis, and synaptic plasticity by phosphorylating key substrates including tau, MAP proteins, and small GTPases 3. CDK5 promotes cell survival through anti-apoptotic pathways and p53 stabilization, while protecting against DNA damage and oxidative stress 4. Dysregulation of CDK5 activity contributes to multiple neurodegenerative diseases. Pathological cleavage of p35 into p25 causes prolonged, aberrant CDK5 activation associated with tau hyperphosphorylation, cytoskeletal disruption, and neuronal death in Alzheimer's disease 5. Reduced CDK5 expression occurs in AD brain tissue, particularly in hippocampus and entorhinal cortex 6. Beyond neurodegeneration, astrocyte-induced CDK5 overexpression in brain metastases suppresses MHC-I expression, enabling immune evasion of cancer cells; CDK5 inhibition with roscovitine enhances checkpoint immunotherapy efficacy 7. Understanding CDK5 regulation and developing selective inhibitors represents a promising therapeutic strategy for neurodegenerative and cancer-related conditions.