Tau Therapeutic Strategies for the Treatment of Alzheimers Disease
Affiliation: Department of DiscoveryResearch, GlaxoSmithKline Medicines Research Centre, Gunnels WoodRoad, Stevenage, Herts, SG1 2NY, UK.
The two classical pathological hallmarks of Alzheimers disease are deposits of aggregated β-amyloid (Aβ ) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition to Aβ pathology, an invariant trait of Alzheimers disease, disruption of tau processing is a necessary event in the neurotoxic cascade which eventually leads to neuronal death and subsequent dementia. Tau is a neuronal, microtubule-bound protein which becomes hyperphosphorylated as a result of an imbalance of the kinase and phosphatase activities which normally tightly regulate its phosphorylation. In addition to this pathogenic hyperphosphorylation, tau dissociates from microtubules and selfaggregates to form insoluble oligomers which progress to the macroscopic tangles evident in post mortem Alzheimers disease tissue. Subsequent toxicity may ensue either as a direct toxic effect of free tau oligomers or as a result of altered microtubule-dependent processes. In order to intervene pharmacologically in this disease process, much effort has been expended in order to identify and inhibit the kinases responsible for pathogenic hyperphosphorylation and many candidate kinases have been investigated including glycogen synthase kinase (GSK-3), cyclin-dependant kinase-5 (Cdk-5), MAPK family members (extracellular signal-regulated kinases 1 and 2 [Erk-1 and 2], MEK [MAP kinase kinase], c-Jun NH2- terminal kinases (JNKs) and p38), casein kinase, calcium calmodulin-dependant kinase II (CaMK-II), microtubule affinity regulating kinase (MARK), protein kinase A (PKA / cAMP-dependant protein kinase) and others. Focus has also fallen upon the role of the phosphatases responsible for dephosphorylation of tau. This review will describe the tau-related etiology of Alzheimers disease and other tauopathies as well as the therapeutic strategies to inhibit the hyperphosphorylation of tau.
Keywords: Tau, MAPT, Alzheimer's disease, microtubule, kinase, Cdk, GSK, MARK
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