UC San Diego

Research toward understanding Alzheimer's disease has revealed that it is strongly linked with metabolic dysfunction, such as that found in Type II Diabetes. For instance, diabetic patients have a doubled risk of developing AD, while Alzheimer's patients have disrupted insulin signaling in the brain. Moreover, some lifestyle modifications beneficial to diabetic patients - specifically, increased physical activity and caloric restriction - have shown promise as tools to manage AD. Both of these interventions create an energy deficit whereby the cellular energy sensor AMPK becomes activated. In turn, AMPK activation promotes energy availability, insulin sensitivity and cellular survival during times of stress. We activated AMPK both pharmacologically and genetically in a transgenic mouse model of AD and measured the effect on learning and memory function by the Morris water maze. Surprisingly, our results revealed a gender- specific response in Alzheimer's phenotypes. Pharmacological activation of AMPK by the anti-diabetic drug metformin in male APP mice worsened learning and memory function. This finding was reproduced with a genetic model of AMPK activation, requiring only liver- specific activity to occur. Remarkably, activation of AMPK in this murine model, either by genetic means or metformin treatment, had beneficial effects for female animals. The results herein demonstrate the effect of AMPK activation in the APP mouse model of AD, the gender-specific differences in cognitive function in response to treatment, the importance of liver function in mental health and the need to assess these factors in human patients as there are currently millions of patients already taking metformin that may be altering their risk of Alzheimer's disease