Evidence for or against CDK5 as a valid target in AD?

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Kent Werner on Mar 16, 2016 • 2 answer
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I'm aware of the literature to a large extent, and I know that this target was actively pursued for several years throughout Pharma. I understand that they stopped working on it due off-target toxicity effects. Can anyone corroborate this and/or provide a supported opinion on CDK5? As a neurologist/scientis treating these patients, I am compelled to explore this target further.

Answers

Dear Kent,
There is discussion on both sides of this issue. The data in favor of targeting Cdk5 relate to its role as a tau kinase and the involvement of its cyclin-like protein p35. The latter is of interest because when a cell under stress lets its calcium levels rise, calpain (a calcium-dependent protease) is activated and p35 is cleaved to p25. This isoform has been reported to hyperactivate Cdk5 and, importantly, to be elevated in AD. The case against Cdk5 has focused on its positive roles in neurodevelopment (where it is essential for migration and maturation), its supporting influence in oligodendrocytes and the negative effects of conditional adult Cdk5 knockouts.

While we don't have clarity yet, I personally think that Cdk5 is a force for good and we inhibit it at our peril. I believe the real danger lies in the activity of GSK3beta and our own recent study showing that p25 binds to it and alters both its substrate specificity and enhances its enzyme activity has only strengthened my sense that Cdk5 is unfairly maligned as a neurotoxic influence.

Hope this helps,
Karl

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Dr. Karl Herrup on Mar 17, 2016
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Dear Karl,
Thank you for your thoughtful answer. Indeed the conditional knockout produced in the Bibb lab at UTSW was revealing both of positive and negative effects. One of my fellow residents in the neurology, David Benavides, developed that mouse, and his thoughts were similar to yours. Thank you also for pointing out the p25-GSK3B interaction study you published in PNAS. Very elegant work, indeed! This begs the question: should we target p25, rather than CDK5?

Best,
Kent

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Kent Werner on Mar 18, 2016
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