Phosphorylating Activity of the Alzheimer's Disease-associated Kinase Cdk5 is Selectively Inhibited ill vitro
Herron, Lisa L.
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Alzheimer's Disease, formally identified nearly 100 years ago by Lois Alzheimer, is easier to diagnose than to treat. As medical advances continue to uncover the biochemical pathways of the disease, two pathogenic aggregates have emerged as common elements in AD brains: amyloid plaques and neurofibrillary tangles. While plaques are extracellular lesions, intracellular tangles are aggregates of the expired neurons themselves. The tangles contain an abnormally hyperphosphorylated version of the microtubule-stabilizing brain protein tau, which is now implicated in AD pathogenesis. Recent research has focused on inhibiting the agents that phosphorylate tau. One such family of agents, the cyclin dependent kinases (Cdk5), is capable of phosphorylating tau, but is more commonly associated with cell cycle regulation. One exception is Cdk5, which is found in an active state exclusively in neurons. The neuronal kinase demonstrates no involvement in cell cycle function and is activated exclusively by p2S, p3S and p39 proteins, rather than by cyclins. Studies of Cdk5 activity have focused on p2S, while less is known regarding the biochemical properties of the CdkS/p3S unit. This investigation first characterized the enzymatic activity of Cdk5/p3S by using a purified GST -tagged Cdk5/p3S enzyme complex. Cdk5 and p3S were then immunoprecipitated from mouse cortex to demonstrate Cdk5 activity in the brain. Finally, both purified and immunoprecipitated forms of Cdk5/p3S were tested for inhibition by several compounds. To demonstrate the inhibitory specificity for both purified and immunprecipitated Cdk5, protein kinase A, a non-Cdk, was also tested and did not demonstrate the same pattern of inhibition. If Cdk5 does mediate hyperphosphorylation of tau in AD, then these potentially specific Cdk5 inhibitors may possess therapeutic potential for treatment of AD and the other neurodegenerative "tauopathies".