Aberrant brain insulin signaling plays a critical role in the pathology of Alzheimer’s disease (AD). Mitochondrial dysfunction plays a role in the progression of AD, with excessive mitochondrial fission in the hippocampus being one of the pathological mechanisms of AD. However, the molecular mechanisms underlying the progression of AD and mitochondrial fragmentation induced by aberrant brain insulin signaling in the hippocampal neurons are poorly understood. Therefore, we investigated the molecular mechanistic signaling associated with mitochondrial dynamics using streptozotocin (STZ), a diabetogenic compound, in the hippocampus cell line, HT-22 cells. In this metabolic dysfunctional cellular model, hallmarks of AD such as neuronal apoptosis, synaptic loss, and tau hyper-phosphorylation are induced by STZ. We found that in the mitochondrial fission protein Drp1, phosphorylation is increased in STZ-treated HT-22 cells. We also determined that inhibition of mitochondrial fragmentation suppresses STZ-induced AD-like pathology. Furthermore, we found that phosphorylation of Drp1 was induced by CDK5, and inhibition of CDK5 suppresses STZ-induced mitochondrial fragmentation and AD-like pathology. Therefore, these findings indicate that mitochondrial morphology and functional regulation may be a strategy of potential therapeutic for treating abnormal metabolic functions associated with the pathogenesis of AD.

异常的脑胰岛素信号传导在阿尔茨海默氏病（AD）的病理中起关键作用。线粒体功能障碍在AD的发展中起作用，海马线粒体过度裂变是AD的病理机制之一。然而，对海马神经元中异常的脑胰岛素信号转导所引起的AD和线粒体片段化进展的分子机制了解甚少。因此，我们在海马细胞系HT-22细胞中使用链脲佐菌素（STZ）（一种致糖尿病化合物）研究了与线粒体动力学相关的分子机制信号。在这种代谢功能异常的细胞模型中，STZ诱导了AD的特征，例如神经元凋亡，突触丧失和tau过度磷酸化。我们发现在线粒体分裂蛋白Drp1中，磷酸化在STZ处理的HT-22细胞中增加。我们还确定，线粒体片段的抑制抑制了STZ诱导的AD样病理。此外，我们发现Drp1的磷酸化是由CDK5诱导的，而抑制CDK5则抑制了STZ诱导的线粒体片段化和AD样病理。因此，这些发现表明线粒体形态和功能调节可能是潜在的治疗与AD发病机理相关的异常代谢功能的策略。抑制CDK5可抑制STZ诱导的线粒体断裂和AD样病理。因此，这些发现表明线粒体形态和功能调节可能是潜在的治疗与AD发病机理相关的异常代谢功能的策略。抑制CDK5可抑制STZ诱导的线粒体断裂和AD样病理。因此，这些发现表明线粒体形态和功能调节可能是潜在的治疗与AD发病机理相关的异常代谢功能的策略。