Diabetes mellitus may cause neurodegeneration, but the exact mechanism by which diabetic conditions induce neuronal cell death remains unclear. Tau protein hyperphosphorylation is considered to be a major pathological hallmark of neurodegeneration and can be triggered by diabetes. Various tau-directed kinases, including P38, can be activated upon diabetic stress and induce tau hyperphosphorylation. Despite extensive research efforts and the known importance of tau pathology in neurodegeneration, the exact tau specie(s) and kinases driving neurodegeneration in diabetes mellitus have not been clearly elucidated. We herein employed protein expression data analysis as well as immunofluorescence and immunoblotting techniques to determine the exact molecular mechanism of tau pathology triggered by diabetes in both primary cultured neurons and type 1 diabetes animal model. We found that P38, a major tau kinase, was increased in Glutamatergic & GABAergic neuron subtypes under diabetic conditions. This rendered them more responsive to oxidative stress caused by diabetes. We observed that oxidative stress activated P38, which in turn directly and indirectly drove tau pathology in the brainstem (enriched by Glutamatergic & GABAergic neurons), which gradually spread to neighboring brain areas. Notably, P38 inhibition suppressed tau pathogenicity and neurodegeneration in diabetic mouse models. The data establish P38 as a central mediator of diabetes mellitus induced tau pathology. Furthermore, the inhibition of P38 at early stages of diabetes-induced stress can inhibit tau pathology. Our findings provide mechanistic insight on the consequences of this metabolic disorder on the nervous system.
Diabetes mellitus (DM) can induce oxidative stress and drive tau pathology in the brainstem that enriched by GABAergic and Glutamatergic neurons. Bioinformatic analysis showed that different genes including MAPK14 (P38) is up-regulated in the GABAergic neurons. Inhibition of the P38 by daily injection of the SB203580 decreased phosphorylated P38 level and suppressed P-tau formation in the brainstem of diabetic mice.