SGLT2 and DPP4 inhibitors improve Alzheimer’s disease‐like pathology and cognitive function through distinct mechanisms in T2D‐AD mouse model

Abstract Background There are common mechanisms between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2D), such as insulin resistance. As insulin signaling has important roles in regulation of neuronal functions in the brain, the hypotheses and theories regarding the pathogenesis of AD implicate brain insulin resistance as a key factor. Also, recent studies demonstrated that sodium‐glucose cotransporter 2 inhibitor (SGLT2‐i) and dipeptidyl peptidase‐4 inhibitor (DPP4‐i) which are T2D drugs have been shown to exert beneficial effects on insulin sensitivity and neuroprotection beyond glucose‐lowering actions. However, in relation to the two drugs, the brain metabolic dysfunction and its mechanisms impaired by insulin resistance have never been investigated. Method We developed T2D‐AD mice model using 60% high‐fat diet for 12 weeks and a single dose of streptozotocin (100 mg/kg/i.p) at week 4 of the diet. Subsequently treated with SGLT2‐i (empagliflozin, 25 mg/kg/day/po) and DPP4‐i (sitagliptin, 100 mg/kg/day/po) for 7 weeks. After behavior tests, expression properties of brain insulin signaling, AD related proteins and drugs action‐associated proteins were examined by using western blotting and immunohistochemistry. Result T2D‐AD mice not only increased blood glucose and body weight, but also had insulin resistance through insulin tolerance test and glucose tolerance test. SGLT2‐i and DPP4‐i were effective in ameliorating insulin sensitivity and reducing body weight gain. In addition, as a result of evaluating hippocampus‐dependent spatial learning and preference memory through behavioral tests, SGLT2‐i and DPP4‐i were found to improve learning, memory, and cognitive functions. Interestingly, SGLT2‐i and DPP4‐i reduced AD‐associated hyperphosphorylated tau (pTau) and amyloid β (Aβ) accumulation in different ways, respectively, along with enhancing brain insulin signaling. SGLT2‐i reduced pTau accumulation through ACE2/Ang(1‐7)/MasR, and DPP4‐i showed an effect of reducing Aβ accumulation by increasing IDE. Conclusion These findings suggested that SGLT2‐i and DPP4‐i prevented AD‐like pathology and cognitive decline by affecting brain insulin signaling through different mechanisms.