P38 initiates degeneration of midbrain GABAergic and glutamatergic neurons in diabetes models

Aisan Farhadi, Mehdi Totonchi, Seyed Masood Nabavi, Hossein Baharvand, Hossein Pakdaman, Ensiyeh Hajizadeh-Saffar, Seyed Ahmad Mousavi, Fatemeh Hadi, Hamed Al-Sinawi, Quan Li, Jin San Zhang*, Yaser Tahamtani*, Koorosh Shahpasand*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Diabetes mellitus may cause tau protein hyperphosphorylation and neurodegeneration, but the exact mechanism by which diabetic conditions induce tau pathology remains unclear. Tau protein hyperphosphorylation is considered 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, the exact tau specie(s) and kinases driving neurodegeneration in diabetes mellitus have not been clearly elucidated. We herein employed different techniques to determine the exact molecular mechanism of tau pathology triggered by diabetes in in vivo and in vitro models. We showed that diabetes-related stresses and glucose metabolism deficiency could induce cis P-tau (an early driver of the tau pathology) accumulation in the midbrain and corpus callosum of the diabetic mice models and cells treated with 2-deoxy-D-glucose, respectively. We found that the active phosphorylated level of P38 was increased in the treated cells and diabetic mice models. We observed that oxidative stress activated P38, which directly and indirectly drove tau pathology in the GABAergic and glutamatergic neurons of the midbrain of the diabetic mice after 96 h, which accumulated in the other neighboring brain areas after 2 months. Notably, P38 inhibition suppressed tau pathogenicity and risk-taking behaviors in the animal models after 96 h. The data establish P38 as a central mediator of diabetes mellitus-induced tau pathology. Our findings provide mechanistic insight into the consequences of this metabolic disorder on the nervous system.

Original languageEnglish
Pages (from-to)3755-3778
Number of pages24
JournalEuropean Journal of Neuroscience
Issue number1
Publication statusPublished - Jul 2022


  • P38
  • diabetes mellitus
  • neurodegeneration
  • tau pathology

ASJC Scopus subject areas

  • Neuroscience(all)


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