Tau kinase inhibitors

Prevention of tau phosphorylation is an additional strategy for AD therapy. The multiple epitopes on tau appear essential to AD pathology, e.g., hyperphosphorylation promotes aggregation and formation of paired helical filaments. Inhibition of the phosphorylation of sites close to the microtubule-binding domain of tau, e.g., pthr231 and pser396, is thought to be critical for preventing tau aggregation, and their hyperphosphorylation has been associated with the incidence of AD. Two kinases identified in the phosphorylation of these sites are CDK-5 and GSK-3b.

CDK-5 (also known as neuronal CDC2-like kinase or NCLK) is a proline-directed serine/threonine kinase present in all tissues; however, its activity is dependent on noncyclin regulatory proteins that are highly expressed in neurons.49 Excessive CDK-5 activity results in neurotoxicity and a pathological event that facilitates increased enzyme activity is proteolysis of its regulatory protein, p35, to a smaller protein p25 by the Ca2 + -dependent enzyme, calpain. Several lines of evidence support a role of CDK-5 in AD pathogenesis: calpain activity is increased in AD brain together with the p25:p35 ratio; overexpression of CDK-5 in primary neurons increases tau phosphorylation at AD-relevant epitopes, and induces cytoskeletal disruption and apoptotic cell death. However, in models of p25 overexpression, NFT formation only occurs with coexpression of mutant tau, suggesting that CDK-5 activity alone is not sufficient for inducing this pathological event. There is no clinical data on small molecule CDK-5 inhibitors. Prototypic compounds include 3'-substituted indolones50 (35) and [1,3,5]triazine-pyridine biheteroaryls51 (36).

GSK-3b (tau protein kinase I, TPK1) is a serine/threonine kinase that constitutively inactivates glycogen synthase.52 GSK-3b is linked to AD pathogenesis via its ability to hyperphosphorylate tau and colocalization with NFTs. Ab exposure of hippocampal neurons activates GSK-3b enhancing tau phosphorylation at multiple sites (Ser181, Ser199, Ser202, Ser396, Ser404, and Ser413). Mice overexpressing GSK-3b show tau hyperphosphorylation in hippocampal and cortical neurons with somatodendritic localization that is accompanied by neuronal death and reactive gliosis and spatial leaning deficits in the Morris water maze. Inhibition of GSK-3b may be beneficial in AD. However, this kinase is also involved in the wnt signaling pathway and b-catenin expression, which is linked to colon cancer and may thus have unacceptable side effects.

Prototype GSK-3b inhibitors include kenpaullones 37, indirubins 38, pyrazolopyrimidines 39, macrocyclic maleimides 40, and thiazoles (e.g., AR-A014418; 41)53.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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