Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) share some pathological features, including tau hyperphosphorylation and deficits in insulin signaling, but the underlying mechanism and effective drugs for treating AD are unknown. The AD-like brain impairments are almost same in both of mouse type 2 DM models induced by the multiple low-dose intraperitoneal (i.p.) streptozotocin (STZ) injection and twice intracerebroventricular (i.c.v.) STZ injection. We found that memory disorders, impairment of insulin signaling, and AD-like tauopathies were exhibited in two different STZ-induced mouse models and that the level of Advanced Glycation End Products (AGEs) was increased in two STZ mouse models. Inhibition of mTORC1 with rapamycin reversed the deficits of insulin signaling associated kinases activity, decreased levels of AGEs and AD-like tau phosphorylation, and also improved memory deficit in both STZ mice. Rapamycin attenuated HG-induced tau hyperphosphorylation via the AKT/AMPK/GSK-3β pathways and p70S6K in SH-SY5Y cells. Taken together, these data demonstrated that rapamycin improved STZ-induced AD-like tauopathies and memory deficit in mice via improving p70S6K and AKT/AMPK/GSK-3β signaling and decreasing AGEs. Therefore, regulating insulin signaling via mTORC1 is a new strategy for preventing T2DM-associated AD, and mTORC1 is a potential drug target.

阿尔茨海默病 (AD) 和 2 型糖尿病 (T2DM) 具有一些病理特征，包括 tau 过度磷酸化和胰岛素信号传导缺陷，但治疗 AD 的潜在机制和有效药物尚不清楚。在由多次低剂量腹腔内 (ip) 链脲佐菌素 (STZ) 注射和两次脑室内 (icv) STZ 注射诱导的两种小鼠 2 型 DM 模型中，AD 样脑损伤几乎相同。我们发现在两种不同的 STZ 诱导的小鼠模型中表现出记忆障碍、胰岛素信号传导障碍和 AD 样 tauopathies，并且在两种 STZ 小鼠模型中晚期糖基化终产物 (AGEs) 的水平增加。用雷帕霉素抑制 mTORC1 逆转了胰岛素信号相关激酶活性的缺陷，降低 AGEs 和 AD 样 tau 磷酸化水平，并改善两只 STZ 小鼠的记忆缺陷。雷帕霉素通过 AKT/AMPK/GSK-3β 通路和 SH-SY5Y 细胞中的 p70S6K 减弱 HG 诱导的 tau 过度磷酸化。综上所述，这些数据表明，雷帕霉素通过改善 p70S6K 和 AKT/AMPK/GSK-3β 信号传导以及降低 AGE 来改善 STZ 诱导的 AD 样 tauo 病和小鼠记忆缺陷。因此，通过 mTORC1 调节胰岛素信号是预防 T2DM 相关 AD 的新策略，而 mTORC1 是一个潜在的药物靶点。这些数据表明，雷帕霉素通过改善 p70S6K 和 AKT/AMPK/GSK-3β 信号传导和降低 AGE 来改善 STZ 诱导的 AD 样 tauo 病和小鼠记忆缺陷。因此，通过 mTORC1 调节胰岛素信号是预防 T2DM 相关 AD 的新策略，而 mTORC1 是一个潜在的药物靶点。这些数据表明，雷帕霉素通过改善 p70S6K 和 AKT/AMPK/GSK-3β 信号传导和降低 AGE 来改善 STZ 诱导的 AD 样 tauo 病和小鼠记忆缺陷。因此，通过 mTORC1 调节胰岛素信号是预防 T2DM 相关 AD 的新策略，而 mTORC1 是一个潜在的药物靶点。