# Body-Wide Glycolytic Shift, Oxidative Stress, and Sex-Specific Effect of Caloric Restriction in a Mouse Model of Alzheimer’s Disease

## TL;DR

This study explores how Alzheimer’s disease affects metabolism and oxidative stress in different organs and how caloric restriction impacts these effects differently in male and female mice.

## Contribution

The study reveals sex-specific metabolic and oxidative changes in Alzheimer’s disease and how caloric restriction modulates these effects in a tissue-specific manner.

## Key findings

- APPPS1 mice showed increased oxidative stress and altered glycolytic enzyme activity in brain, liver, and kidney compared to wild-type mice.
- Caloric restriction had sex-specific effects, intensifying lipid peroxide accumulation in some organs while reducing it in others.
- CR potentiated glycolysis and modulated glutathione-dependent enzymes in a sex-dependent manner.

## Abstract

Alzheimer’s disease (AD) is regarded as a disease of the brain. Cumulative evidence increasingly supports a full-body view on this disorder, with the liver and kidneys playing an important role in amyloid clearance. The latter is likely potentiated by caloric restriction (CR), whose impact on the metabolism of amyloid-handling tissues is poorly understood. We studied the sex-specific effects of amyloidosis and CR on oxidative and metabolic processes in APPPS1 mice that express amyloidogenic proteins. Wild-type (WT) and APPPS1 mice were either fed ad libitum (AL) or received 70% of their AL caloric intake (CR). Compared to age-matched WT controls, the brain, liver, and kidney of 9-month-old AL APPPS1 mice exhibited higher levels of oxidative stress markers, higher superoxide dismutase, and lower catalase activities. These differences were sex- and tissue-specific, with kidneys showing the largest AD-induced differences between sexes. In addition, APPPS1 mice possessed higher pyruvate kinase activity than WT mice in all organs and higher hexokinase and phosphofructokinase activities in the brain, with stronger effects in males. CR intensified the accumulation of lipid peroxides in the liver and the female brain but decreased it in the female kidney. CR potentiated glycolysis, predominantly in females and modulated glutathione-dependent enzymes, in a sex-dependent manner.