BENEFICIAL EFFECTS OF PROTEIN RESTRICTION ON METABOLIC HEALTH, COGNITIVE FUNCTION AND NEUROPATHOLOGY IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Abstract

AbstractBackgroundAge is the greatest risk factor in developing Alzheimer’s Disease (AD); hence, there is great interest in the possibility of targeting AD through interventions that slow or delay aging. Dietary protein restriction (PR) has been shown to be beneficial in improving overall healthspan in both humans and mice. However, the effect of PR in delaying the symptom progression of AD is largely unknown. In this study, we sought to determine the effects of PR in improving metabolic dysfunction, cognitive deficits and AD pathology along with examining the role of mTORC1 and its downstream targets in the 3xTg mouse model of AD.MethodSix 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 15 months to determine their effects on cognition, metabolic health and AD neuropathology. Cognitive functioning was assessed via Novel Object Recognition (NOR) test and Barnes maze test.ResultFemale 3xTg‐AD mice on PR diet showed improved long‐term memory (LTM), and males showed a positive trend in improved cognitive function compared with their age matched controls. Based on latency measurements in Barnes maze, we found that a PR diet substantially improved spatial memory in both male and female 3xTg mice. 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). Histopathological analysis of the hallmarks of AD showed that mice on PR had decreased tau phosphorylation and Aß plaques. Phosphorylation of the mTORC1 substrate S6K1 was decreased in PR fed 3xTg mice which suggest that reduced mTORC1 signaling may be mediating the beneficial effects of PR on AD pathology. We also found that levels of p62 protein, the major autophagy cargo receptor, is increased in 3xTg AD mice and following PR, decreased p62 expression was observed, suggesting that PR activates autophagy.ConclusionThese results suggests the molecular interplay between mTORC1 and autophagy in PR mediated beneficial effects in diminishing AD pathology.