Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

Background: Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer's disease, including increased expression of beta-amyloid protein (A beta) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of A beta protein, tau phosphorylation, and inflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method: An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of A beta protein, tau phosphorylation, and inflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results: These results showed that minocycline decreased expression of A beta protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion: On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of A beta generation, the decreases in A beta production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to A beta production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and A beta to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer's disease.