Restriction of dietary protein slows the development and progression of Alzheimer’s disease in 3xTg mice

Abstract

AbstractBackgroundCaloric restriction (CR) promotes health and longevity in diverse species and has been successful in ameliorating Alzheimer’s disease (AD) pathology in mouse models and non‐human primates. However, CR may be difficult to adhere to, which makes the reduction of specific macronutrients without restricting calories an attractive alternative. Low protein intake is associated with healthy aging and reduced mortality in humans, and protein restriction (PR) extends the lifespan and healthspan of many mouse models. In this study, we examined the effects of PR on metabolic health and AD pathology in the 3xTg mouse model of AD.MethodWe placed male and female 3xTg mice as well as non‐transgenic (NTg) controls on either a Control diet (21% of calories from protein) or a PR diet (7% of calories from protein) starting at 6 months of age. We assessed the effect of PR on metabolic health, cognition, and AD neuropathology along with targeted metabolomics on plasma samples to identify the abundance of metabolites and dysregulated metabolic pathways.ResultWe found that a long‐term PR diet had substantial metabolic benefits for both male and female 3xTg and NTg mice, promoting leanness and glycemic control. We also found that consumption of low protein diet significantly improved cognitive performance and reduced multiple aspects of AD neuropathology including tau phosphorylation, Aß plaques and gliosis. Phosphorylation of the mTORC1 substrate S6K1 was decreased and the major autophagy cargo receptor P62 was increased in PR‐fed 3xTg mice, which suggests that reduced mTORC1 signaling may mediate the beneficial effects of PR on AD pathology. Targeted metabolomics revealed that several metabolites involved in nucleic acid metabolism and amino acid metabolism were altered between control fed and PR fed mice in a sex specific manner.ConclusionOur findings suggest that lowering dietary protein may be a novel way to slow or even prevent AD. In addition, drugs that mimic the effects of PR may be an effective pharmaceutical approach to combat AD pathology.