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Cited by 79Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models

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Naia, Luana, Shimozawa, Makoto, Bereczki, Erika, Li, Xidan, Liu, Jianping, Jiang, Richeng, Giraud, Romain, Leal, Nuno Santos +6 more·2023·Molecular Psychiatry
DOI 10.1038/s41380-023-02289-4PMC PMC10730401
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Abstract

Accumulation of amyloid β-peptide (Aβ) is a driver of Alzheimer’s disease (AD). Amyloid precursor protein ( App ) knock-in mouse models recapitulate AD-associated Aβ pathology, allowing elucidation of downstream effects of Aβ accumulation and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in App NL-F and App NL-G-F knock-in mice by time-course transcriptome analysis of hippocampus, a region severely affected in AD. Strikingly, energy metabolism emerged as one of the most significantly altered pathways already at an early stage of pathology. Functional experiments in isolated mitochondria from hippocampus of both App NL-F and App NL-G-F mice confirmed an upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, associated with higher susceptibility to oxidative damage and Ca 2+ -overload. Upon increasing pathologies, the brain shifts to a state of hypometabolism with reduced abundancy of mitochondria in presynaptic terminals. These late-stage mice also displayed enlarged presynaptic areas associated with abnormal accumulation of synaptic vesicles and autophagosomes, the latter ultimately leading to local autophagy impairment in the synapses. In summary, we report that Aβ-induced pathways in App knock-in mouse models recapitulate key pathologies observed in AD brain, and our data herein adds a comprehensive understanding of the pathologies including dysregulated metabolism and synapses and their timewise appearance to find new therapeutic approaches for AD.

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  • A recent study showed that APP KI mice display mitochondrial hypermetabolism before the onset of any pathology.

    “This is further supported by a recent study showing that APP KI mice display mitochondrial hypermetabolism before the onset of any pathology.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [49]

    The Introduction (page not provided) reports mitochondrial hypermetabolism in App knock-in mice before the establishment of Aβ pathology, and the Discussion describes it as preceding neuroinflammation and autophagic decline. The source does not establish that it occurs before *any* pathology; it describes altered energy metabolism as an early-stage pathological change. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Upon increasing pathologies, the brain shifted to a state of hypometabolism.

    “Upon increasing pathologies, the brain shifted to a state of hypometabolism [49].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [49]

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Cited by

Sorted by citations

Authors
Naia, L., Shimozawa, M., Bereczki, E., Li, X., Liu, J., Jiang, R., Giraud, R., Leal, N. S., Pinho, C. M., Berger, E., Falk, V. L., Dentoni, G., Ankarcrona, M., & Nilsson, P.
Affiliations
  • Karolinska Institutet (SE)
  • University of Bern (CH)
Corresponding author
  • Ankarcrona, Maria
  • Nilsson, Per
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2023-09
Volume
28
Issue
9
Pages
3966-3981
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-023-02289-4
PMC
PMC10730401
OpenAlex
W4388075101
Cited by
79
References
13
Citations by year
2026: 26 · 2025: 28 · 2024: 23 · 2023: 2
FWCI
13.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • BORIS (University Library Bern) (submittedVersion, cc-by)
  • Open Access CRIS of the University of Bern
Funders
  • Vetenskapsrådet
  • Familjen Erling-Perssons Stiftelse
  • Alzheimerfonden
  • Gun och Bertil Stohnes Stiftelse
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloid-beta, amyloid precursor protein, APP knock-in mice, oxidative phosphorylation, mitochondrial dysfunction, oxidative damage, calcium overload, hippocampus, presynaptic terminals, autophagy dysfunction, synaptic vesicles, autophagosomes, energy metabolism, disease progression
MeSH terms
Alzheimer Disease, Animals, Autophagy, Disease Models, Animal, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Mobile Applications

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