# Sex-specific changes in energy demand during the preplaque stage in a transgenic Alzheimer’s mouse model

## TL;DR

This study finds that female mice with a model of Alzheimer's disease show increased energy use and mitochondrial changes before symptoms appear, which may explain their higher risk of early death.

## Contribution

The study reveals sex-specific metabolic changes in preplaque Alzheimer’s mice, particularly in females, linking energy imbalance to increased mortality.

## Key findings

- Preplaque APP23 female mice show increased hepatic mitochondrial respiration and energy expenditure.
- Female APP23 mice have higher activity and lower calorie intake, leading to a negative energy balance.
- APP23 females exhibit increased fecal energy loss and reduced survival compared to males.

## Abstract

Cognitive deficits and brain glucose hypometabolism, lipid peroxidation and mitochondrial dysfunction are early pathological events in murine models and patients with Alzheimer’s disease (AD). Data from our previous research indicate that transgenic mice of the APP23 line, a murine AD model, exhibited higher energy expenditure and mitochondrial dysregulation in the liver as early as 3 months of age, which is considered the preplaque stage. Since women have a higher risk and mortality rate for AD, with potential sex-specific confounders as longevity, biological, genetic, and social factors also needing to be considered, sex differences in energy metabolism in AD remain insufficiently investigated.

Here, we investigated sex-specific differences in mitochondrial respiration and metabolic profiles of 3–4-month-old, preplaque APP23 transgenic mice, in which we did not detect inflammatory signals and pathological amyloid-beta (Aß) plaques in brain or liver. Their mitochondrial respiration was assessed measuring oxygen consumption rates in isolated primary hepatocytes, stromal vascular cells (SVCs) and re-differentiated adipocytes. Furthermore, we analyzed energy balance, including food intake, locomotor activity, energy expenditure and fecal calorie loss.

We observed an upregulation of hepatic mitochondrial respiration in preplaque APP23 females. Female-derived SVCs and differentiated adipocytes improved mitochondrial flexibility with palmitate loading in vitro, which was in line with decreased plasma triglycerides in preplaque APP23 females in vivo. However, no differences in mitochondrial respiration were detected in hepatocytes and re-differentiated adipocytes derived from male APP23 mice. Furthermore, we corroborated an increased mortality during the preplaque stage, particularly in females, which exhibited reduced hyperactivity and caloric intake before death compared to survivors.

Our data demonstrate that preplaque APP23 female mice have disequilibrated mitochondrial oxidation in hepatocytes and adipocytes as well as higher energy expenditure due to increased activity before AD manifestation. In contrast, male APP23 mice did not exhibit such metabolic changes. Constant excessive energy loss and limited calorie supply potentially contribute to the higher risk of mortality, especially in APP23 females during young adulthood.

Alzheimer’s disease (AD) affects men and women differently, with women at higher risk and mortality. This study explored sex differences in energy metabolism using APP23 transgenic mice, a model of AD, at young age (3–4 months) - before pathological amyloid-beta (Aß) plaques develop in the brain and liver. Female APP23 mice showed increased mitochondrial activity in liver and fat cells, higher energy expenditure, and more movement while eating less. They also excreted more energy in their feces. Notably, female APP23 mice had a lower survival rate than males. Before death, they became less active and ate even less, suggesting an inability to maintain energy balance. These findings indicate that female APP23 mice experience excessive energy loss, which may contribute to early mortality. Understanding these sex-specific metabolic differences could provide new insights into AD progression and highlight the need for targeted treatments.

The online version contains supplementary material available at 10.1186/s13293-025-00737-0.

AD-related inflammatory signals and pathological Aβ plaques are virtually absent in the brain and liver of young APP23 mice in the preplaque stage.

Preplaque APP23 transgenic female mice upregulate hepatic mitochondrial respiration, which is not observed in APP23 males.

Ex vivo differentiated adipocytes isolated from preplaque APP23 females exhibit increased mitochondrial flexibility to fatty acid-induced metabolic stress.

The preplaque APP23 females show increased activity with lower diet intake, while both sexes of APP23 mice have higher fecal energy loss compared to wild-type controls.

The negative energy balance could contribute to the increased premature mortality of young APP23 mice in the preplaque stage.

The online version contains supplementary material available at 10.1186/s13293-025-00737-0.