Effect of geroprotectors on metabolic health and cognitive function in a mouse model of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is the most common form of dementia and is rapidly growing in prevalence as the population grays. As AD is a disease of aging, and other diseases of aging including diabetes and obesity are risk factors for AD, geroprotective interventions may be use in preventing, treating or delaying the progression of AD. Here, we report our preliminary results of our investigation into the effects of geroprotectors and dietary interventions including protein restriction (PR), acarbose and rapamycin on cognition and disease pathology in the 3xTg mouse model of AD. Six month old male and female 3xTg-AD mice were placed on either 21% protein (control) or 7% protein (PR) diets starting from 6 months and continued until 11 months to determine their effects on AD pathology, metabolic health and cognition. We find that males differed in body weight after only 4 weeks of PR, but females did not differ in body weight even after 12 weeks of PR. Cognitive functioning was analyzed via Novel Object Recognition test. Female's 3xTg-AD mice on PR diet showed improved long-term memory (LTM), but no significant improvement in short-term memory test (STM), and males showed a positive trend in improved cognitive function compared with their age matched controls. Female and male mice on low protein diets exhibited improvement in glucose tolerance, however females showed a stronger effect in glycemic control than males following a glucose tolerance test (GTT). Following rapamycin or acarbose (from 6 - 9 months) treatment male mice showed decreased AMPK phosphorylation and p62 levels in the brain, as well as a trend toward decreased tau phosphorylation which is a marker for AD progression and reduced expression of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the brain. Our results are promising and suggests that geroprotectors showed beneficial effects on metabolic health, cognitive functioning and a reduction in AD progression markers. However more research is needed and we will further report on ongoing studies, which shows that use of geroprotectors as therapies for AD has significant potential, and can provide additional insights into the mechanisms of action by which geroprotectors function.