Chronic Stress Induces Hippocampal Mitochondrial Damage in APPPS1 Model Mice and Wildtype Littermates

Amalie Clement, Marianne Juul Madsen, Kenneth Kastaniegaard, Ove Wiborg, Ayodeji A Asuni, Allan Stensballe

Research output: Contribution to journalJournal articleResearchpeer-review

1 Citation (Scopus)


BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. Despite decades of investigation, the etiology of AD is not fully understood, although emerging evidence suggest that chronic environmental and psychological stress plays a role in the mechanisms and contributes to the risk of developing AD. Thus, dissecting the impact of stress on the brain could improve our understanding of the pathological mechanisms.

OBJECTIVE: We aimed to study the effect of chronic stress on the hippocampal proteome in male APPPS1 transgenic mice and wildtype (WT) littermates.

METHODS: APPPS1 and WT mice were subjected to 4 weeks of chronic stress followed by 3 weeks of continued diurnal disruption. Hippocampal tissue was used for proteomics analysis using label-free quantitative DIA based LC-MS/MS analysis.

RESULTS: We identified significantly up- and downregulated proteins in both APPPS1 and WT mice exposed to chronic stress compared to the control groups. Via interaction network mapping, significant proteins could be annotated to specific pathways of mitochondrial function (oxidative phosphorylation and TCA cycle), metabolic pathways, AD pathway and synaptic functions (long term potentiation). In WT mice, chronic stress showed the highest impact on complex I of the oxidative phosphorylation pathway, while in APPPS1 mice this pathway was compromised broadly by chronic stress.

CONCLUSION: Our data shows that chronic stress and amyloidosis additively contribute to mitochondrial damage in hippocampus. Although these results do not explain all effects of chronic stress in AD, they add to the scientific knowledge on the topic.

Original languageEnglish
JournalJournal of Alzheimer's Disease
Issue number1
Pages (from-to)259-272
Number of pages14
Publication statusPublished - 3 May 2022

Bibliographical note

This work was partly founded by the Innovation Fund Denmark under the grant file number 7038-00103B. We further acknowledge Obelske Family Foundation, Svend Andersen Foundation and Spar Nord Foundation for grants that supported the analytical platform which enabled this study. Likewise, we are grateful to the Danish Agency for Science & Higher Education for the funding to support the Danish National Mass Spectrometry Platform for Functional Proteomics (PRO-MS; Grant no. 5072-00007B). Ditte Bech Laursen (Aalborg University), Anett Ravn Neve and Rie Christensen (H. Lundbeck A/S) are acknowledged for technical assistance.


  • Alzheimer Disease/pathology
  • Animals
  • Chromatography, Liquid
  • Disease Models, Animal
  • Hippocampus/pathology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Tandem Mass Spectrometry
  • mitochondrial function
  • hippocampus
  • proteomics
  • oxidative phosphorylation
  • mass spectrometry
  • chronic stress
  • Alzheimer's disease


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