Akiko Taguchi
The aging systemic milieu leads to a decline in hippocampal neurogenesis and cognitive functions, which also occurs in diabetes. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Metformin, a biguanide anti-diabetic medication is the firstline drug for type-2 diabetes and lowers blood glucose levels by decreasing basal hepatic glucose output and increasing glucose uptake by skeletal muscle through activation of the AMP-Activated Protein Kinase (AMPK). Here we show that prolonged treatment with metformin enhances hippocampal neurogenesis while countering the microglial activation in the context of the combination of aging and diabetes in mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes, it improves hippocampal-dependent spatial memory functions accompanied by increased serine/threonine phosphorylation of AMPK, Atypical Protein Kinase C ζ (aPKC ζ) and Insulin Receptor Substrate 1 (IRS1), a major mediator of the insulin/IGF1R signaling, in the hippocampus. Our findings suggest that signaling networks acting through long-term metformin-stimulated phosphorylation of AMPK, aPKC ζ/λ and IRS1 serine sites contribute to neuro-protective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect. Introduction: Adult neurogenesis occurs throughout life in specific brain regions of mammals, including the hippocampus and subventricular zone. Alterations in hippocampal neurogenesis are associated with neurological and psychiatric disorders, such as epilepsy, Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease (HD), and depression. In addition, the systemic milieu in the context of aging leads to a decline in hippocampal neurogenesis and cognitive functions in animals, which also occurs in model animals with type 1 or type 2 diabetes such as streptozotocin