Cdk5 Activation and Tau Phosphorylation

Of the characteristic plaques and tangles in Alzheimer’s disease, the tangles are principally composed of a protein called Tau. In disease states, Tau proteins accumulate extra chemical modifications, termed phosphorylation. Dr. Lee and his colleagues have identified a specific protein that may be responsible for phosphorylation. By understanding how to influence the activity of this protein, they are preparing a strategy to ultimately prevent a major cause of the ‘tangles’ seen in people with Alzheimer’s disease.

Cyclin-dependent kinase 5 (Cdk5) is a small enzyme that has been associated mostly with the activity of neurons. Cdk5 contributes to the major kinase activity in neurons and has been implicated in altering the state of neuron-specific Tau proteins by making them “hyperphosphorylated.” Hyperphosphorylated Tau is the major component of paired helical filaments (PHFs) that constitute larger structures (such as NFTs) in AD. Although other enzymes can alter the state of Tau, Cdk5 is a major candidate responsible for Tau hyperphosphorylation. For its activity, Cdk5 requires either a protein called p35nck5a, or a related protein called p39nck5ai, or their shorter forms, p25nck5a and p3Onck5ai, respectively. In a recent study, it was shown that Cdk5 activation by p25nck5a can be enhanced by a neuronal cell extract, suggesting the existence of a Cdk5-activating kinase, which has been named Cdk5-AK. Dr. Lee is exploring the hypothesis that Cdk5 is regulated primarily by its activators, nck5a and nck5ai, and an upstream Cdk5-AK. He also believes that abnormal regulation of Cdk5 contributes to hyperphosphorylation of Tau and neuronal cell death in AD. In this study, Dr. Lee hopes to (1) identify and characterize a Cdk5-AK and (2) to characterize the various Cdk5/activator complexes and their ability to phosphorylate Tau. If successful, these studies will further our understanding of how Cdk5 activity is regulated in the brain and how the enzyme may participate in the development of AD.