Cyclin dependent kinase 5 regulatory subunit 1 (CDK5R1) is a 35 kDa protein that associates with and activates CDK5. Its expression is restricted to neurons and is required for normal brain development. CDK5R1 can be cleaved by calpain at Phe98-Ala99 which liberates a C-terminal fragment known as p25. p25 induces prolonged activation of CDK5 and broadens the substrate specificity of CDK5 to include tau which is aberrantly phosphorylated in Alzheimers disease. Full length CDK5R1 is myristoylated at Gly2 and is preferentially localized to membranes at the cell periphery. p25 lacks this modification and is enriched in the nucleus and perinuclear regions. p25 accumulates in the brains of Alzheimers patients where it promotes neuronal apoptosis and cytoskeletal abnormalities.