Activity of the neuronal Cdc2-like kinase composed of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, is critical for the normal development of the central nervous system, including cortical lamination and axonal patterning events. Conversely, altered Cdk5 activity has been associated with several neuronal defects including neurodegeneration. Indeed, an increasing line of evidence suggests that Cdk5 contributes to neurodegeneration in AD. For example, Cdk5 immunoreactivity is consistently detected in neurofibrillary tangles (NFTs) [15]; Cdk5 phosphorylates tau and promotes dimerization of tau to an AD-like state [2, 13]; sulfated glycosaminoglycans co-exist with tau and Cdk5 in NFTs and remarkably enhance tau phosphorylation by Cdk5 [5]; protein phosphatase 1 (PP1), which shows decreased activity in AD brains [4], is inhibited by Cdk5 through phosphorylation of the PP1 inhibitor protein (I-1) [6]; in primary neuronal cultures, Aβ induces activation of Cdk5 that results in tau hyperphosphorylation, cytoskeletal collapse, and cell death [1, 9]. In addition, we and others have shown elevated Cdk5 activity in mice exhibiting tau hyperphosphorylation [10], and in AD brains [7,11]. However, the molecular mechanisms whereby Cdk5 activity is upregulated in AD brain remain to be investigated. Recently, it was suggested that Cdk5 activity is enhanced by calcium through induction of p35 cleavage to p25 via calpain activation [9]. The active truncated form of p35, p25, was then shown to accumulate in