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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. [ABSTRACT FROM AUTHOR]

Parkinson disease (PD) is the second most common neurodegenerative disorder, whose prevalence is 2~3% in the population over 65. α‐Synuclein aggregation is the major pathological hallmark of PD. However, recent studies have demonstrated enhancing evidence of tau pathology in PD. Despite extensive considerations, thus far, the actual spreading mechanism of neurodegeneration has remained elusive in a PD brain. This study aimed to further investigate the development of α‐synuclein and tau pathology. We employed various PD models, including cultured neurons treated with either 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) or with recombinant α‐synuclein. Also, we studied dopaminergic neurons of cytokine Interferon‐β knock‐out. Moreover, we examined rats treated with 6‐hydroxydopamine, Rhesus monkeys administrated with MPTP neurotoxin, and finally, human post‐mortem brains. We found the α‐synuclein phosphorylation triggers tau pathogenicity. Also, we observed more widespread phosphorylated tau than α‐synuclein with prion‐like nature in various brain areas. We optionally removed P‐tau or P‐α‐synuclein from cytokine interferon‐β knock out with respective monoclonal antibodies. We found that tau immunotherapy suppressed neurodegeneration more than α‐synuclein elimination. Our findings indicate that the pathogenic tau could be one of the leading causes of comprehensive neurodegeneration triggered by PD. Thus, we can propose an efficient therapeutic target to fight the devastating disorder. [ABSTRACT FROM AUTHOR]

The Wnt pathway is the most important cascade in the nervous system; evidence has indicated that deregulation of the Wnt pathway induced pathogenic hallmarks of neurodegenerative diseases. Glycogen synthase kinase‐3β (GSK‐3β) as the main member of the Wnt pathway increases tau inclusions, the main marker in the neurodegenerative diseases. Phosphorylated tau is observed in the pre‐tangle of the neurons in the early stage of neurodegenerative diseases. The researchers always try to improve pharmacological approaches of new therapeutic strategies to the treatment of neurodegenerative diseases that are required to represent a significant entry point by understanding the theoretical interactions of the molecular pathways. In this review, we have discussed the recent knowledge about the canonical and non‐canonical Wnt signalling pathway, GSK‐3β, Wnt/β‐catenin antagonists, tau phosphorylation, and their important roles in the neurodegenerative diseases. [ABSTRACT FROM AUTHOR]