Tau kinase signaling pathway

Tau kinase–related signaling refers to the complex network of intracellular enzymes, primarily kinases, that regulate the phosphorylation state of the microtubule-associated protein Tau (MAPT) (Hanger et al., 2009, Trends Mol Med). Key kinases involved in this pathway include Glycogen Synthase Kinase 3 beta (GSK-3β), Cyclin-Dependent Kinase 5 (CDK5), and Fyn, which modulate Tau's affinity for microtubules and its role in axonal transport (Hernandez et al., 2013, Mol Neurobiol). Under physiological conditions, these kinases maintain a precise balance of Tau phosphorylation necessary for neuronal cytoskeletal integrity. In neurodegenerative diseases like Alzheimer's and other tauopathies, aberrant activation of these kinases leads to Tau hyperphosphorylation, causing it to detach from microtubules and aggregate into toxic neurofibrillary tangles (Mazanetz & Fischer, 2007, Nat Rev Drug Discov). Therapeutic strategies targeting this signaling network aim to inhibit specific kinases to reduce Tau pathology and preserve cognitive function. Drugs such as Tideglusib and Saracatinib have been evaluated in clinical trials for their potential to modify disease progression by targeting these kinases (Lovestone et al., 2014, J Alzheimers Dis; Nygaard et al., 2015, JAMA Neurol). However, the pleiotropic roles of these kinases in vital processes like glucose metabolism and cell signaling present significant challenges for drug selectivity and safety.

Other names

Tau phosphorylation pathwayTau protein kinase signalingTPK signalingMicrotubule-associated protein tau signaling

Inhibition of specific kinases such as Glycogen Synthase Kinase 3 beta (GSK-3β), Cyclin-Dependent Kinase 5 (CDK5), and Fyn to reduce the hyperphosphorylation of Tau protein, thereby preventing the formation of neurofibrillary tangles and maintaining microtubule stability (Mazanetz & Fischer, 2007, Nat Rev Drug Discov).