Dietary-challenged mice with Alzheimer-like pathology show increased energy expenditure and reduced adipocyte hypertrophy and steatosis

Aging (Albany NY). 2021 Apr 16;13(8):10891-10919. doi: 10.18632/aging.202978. Epub 2021 Apr 16.


Alzheimer's disease (AD) is frequently accompanied by progressing weight loss, correlating with mortality. Counter-intuitively, weight loss in old age might predict AD onset but obesity in midlife increases AD risk. Furthermore, AD is associated with diabetes-like alterations in glucose metabolism. Here, we investigated metabolic features of amyloid precursor protein overexpressing APP23 female mice modeling AD upon long-term challenge with high-sucrose (HSD) or high-fat diet (HFD). Compared to wild type littermates (WT), APP23 females were less prone to mild HSD-induced and considerable HFD-induced glucose tolerance deterioration, despite unaltered glucose tolerance during normal-control diet. Indirect calorimetry revealed increased energy expenditure and hyperactivity in APP23 females. Dietary interventions, especially HFD, had weaker effects on lean and fat mass gain, steatosis and adipocyte hypertrophy of APP23 than WT mice, as shown by 1H-magnetic-resonance-spectroscopy, histological and biochemical analyses. Proteome analysis revealed differentially regulated expression of mitochondrial proteins in APP23 livers and brains. In conclusion, hyperactivity, increased metabolic rate, and global mitochondrial dysfunction potentially add up to the development of AD-related body weight changes in APP23 females, becoming especially evident during diet-induced metabolic challenge. These findings emphasize the importance of translating this metabolic phenotyping into human research to decode the metabolic component in AD pathogenesis.

Keywords: Alzheimer's disease; diet-induced obesity; energy expenditure; hypertrophy; steatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / pathology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / pathology
  • Diet, High-Fat / adverse effects
  • Dietary Sucrose / administration & dosage
  • Dietary Sucrose / adverse effects
  • Disease Models, Animal
  • Energy Metabolism / genetics
  • Fatty Liver / diagnosis*
  • Fatty Liver / etiology
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Female
  • Glucose Intolerance / diagnosis*
  • Glucose Intolerance / etiology
  • Glucose Intolerance / metabolism
  • Glucose Intolerance / pathology
  • Humans
  • Hypertrophy / diagnosis
  • Hypertrophy / etiology
  • Hypertrophy / metabolism
  • Hypertrophy / pathology
  • Liver / pathology
  • Mice
  • Mice, Transgenic
  • Severity of Illness Index


  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Dietary Sucrose