National Center for Geriatrics and Gerontology, Japan
Title: Metformin enhances neurogenesis and memory function via hippocampal insulin signaling independent of the hypoglycemic effect
Dr. Taguchi obtained her B.Sc. from Tokyo University of Agriculture, in Tokyo, Japan and her Ph.D. from Osaka University Graduate School of Medicine, in Osaka, Japan. She worked as a postdoctoral research fellow and a research associate in Dr. Morris White’s lab at Harvard Medical School, Boston, USA. Dr. Taguchi is interested in the interaction between lifestyle-related diseases such as diabetes and neurological disorder such as dementia. Her lab currently studies on the molecular mechanism of diabetes-associated cognitive decline. She is particularly interested in the roles of neural insulin/IGF1R signaling in cognitive functions and the effects of existing medications on brain functions (drug repositioning ). Dr. Taguchi has received several grants from Grant-in-Aid for Scientific Research on Innovative Areas, Grant-in-Aid for Scientific Research, Grant-in-Aid for challenging Exploratory Research, and private foundations in Japan.
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 antidiabetic medication is the first-line 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 neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.