TYK2 Inhibition as a Basis for Treating Tauopathies Such as Alzheimer's Disease
Alzheimer's disease progresses through stages. The well known, slow accumulation of misfolded amyloid-β over years is only the early foundation of the condition, in and of itself producing little more than mild cognitive impairment. Amyloid-β, however, enables the onset of a state of chronic inflammation and tau protein aggregation that feeds upon itself and grows in severity, disrupting function and killing brain cells until it ultimately kills the patient. Researchers here find a potential target to slow or prevent the aggregation of altered tau protein in mouse models. Since these models are highly artificial, as aged mice do not normally suffer anything resembling a tauopathy, further work will be needed to demonstrate relevance to the natural human condition of Alzheimer's disease.
Over two dozen different diseases have been identified so far whose hallmark neuropathological feature is the presence of neuronal and/or glial accumulations of tau protein. Tau is a predominantly neuronal protein that binds to tubulin to promote assembly of the microtubule network that underpins intracellular transport. Its function is regulated by numerous post-translational modifications, such as phosphorylation, ubiquitination, and acetylation. In pathological states, tau protein undergoes aberrant modifications - predominantly hyperphosphorylation - then dissociates from microtubules, misfolds, propagates to neighboring cells and accumulates into intracellular neurofibrillary tangles (NFTs).
Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.