Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice
Abstract
Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer's disease integrating genetic factors related to enhanced amyloid-beta (Ass) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Ass pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Ass deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Ass. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Ass dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Ass and progression accelerates substantially with aging.
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Membrane depolarization, decreased ATP levels, decreased COX activity and increased ROS levels occur before extracellular Aβ deposition and aggravate with age, in mitochondria isolated from AβPPSL transgenic mice.
“membrane depolarization, decreased ATP levels, decreased COX activity and increased ROS levels occur before extracellular Aβ deposition and aggravate with age. These data were obtained in mitochondria isolated from AβPPSL transgenic mice [68]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [68]
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- Authors
- Hauptmann, S., Scherping, I., Dröse, S., Brandt, U., Schulz, K. L., Jendrach, M., Leuner, K., Eckert, A., & Müller, W. E.
- Affiliations
- Goethe University Frankfurt (DE)
- Universitäre Psychiatrische Kliniken Basel (CH)
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 30
- Issue
- 10
- Pages
- 1574-1586
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2071276938
- Cited by
- 469
- References
- 3
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 16 · 2023: 34 · 2022: 24 · 2021: 41 · 2020: 24 · 2019: 26 · 2018: 29 · 2017: 18 · 2016: 26 · 2015: 17 · 2014: 30 · 2013: 29 · 2012: 36
- FWCI
- 19.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- 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
- mitochondrial dysfunction, Alzheimer's disease, amyloid-beta, APP transgenic mice, aging, mitochondrial membrane potential, reactive oxygen species, cytochrome c oxidase subunit IV, mitochondrial respiration, intracellular amyloid-beta, early pathogenesis
- MeSH terms
- Adenosine Triphosphate, Aging, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Electron Transport, Female, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Receptors, Cell Surface, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Reactive Oxygen Species, Oxidative Stress, Mitochondrial Diseases, bcl-X Protein, bcl-2-Associated X Protein, Mice, Membrane Potential, Mitochondrial, Protease Nexins
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