Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease
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Abstract In the mitochondria-mediated vicious cycle of Alzheimer’s disease (AD), intracellular amyloid β (Aβ) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Aβ accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA). Expression of hTFAM significantly improved cognitive function, reducing accumulation of both 8-oxoguanine, an oxidized form of guanine, in mtDNA and intracellular Aβ in 3xTg-AD mice and increasing expression of transthyretin, known to inhibit Aβ aggregation. Next, we found that AD model neurons derived from human induced pluripotent stem cells carrying a mutant PSEN1 (P117L) gene, exhibited mitochondrial dysfunction, accumulation of 8-oxoguanine and single-strand breaks in mtDNA, and impaired neuritogenesis with a decreased expression of transthyretin, which is known to be downregulated by oxidative stress. Extracellular treatment with recombinant hTFAM effectively suppressed these deleterious outcomes. Moreover, the treatment increased expression of transthyretin, accompanied by reduction of intracellular Aβ. These results provide new insights into potential novel therapeutic targets.
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Amyloid oligomers can access mitochondria, contributing to compromised mitochondrial function and triggering a vicious circle in which it is not defined whether Aβ accumulation precedes or follows mitochondrial decline.
“Besides, amyloid oligomers can access mitochondria, contributing to compromise their function and triggering a vicious circle in which it is not defined if the accumulation of Aβ came before mitochondrial declined function or after [67].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [67]
Excessive Ca2+ accumulation into mitochondria leads to decreased mitochondrial membrane potential and increased reactive oxygen species production in the APP/PS1 Alzheimer's disease mouse model.
“Excessive Ca2+ accumulation into mitochondria leads to decreased mitochondrial membrane potential and increased ROS production in the same AD mouse model [67,68,70].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [67]
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Modeling Alzheimer’s disease with iPSC-derived brain cells
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- Authors
- Oka, S., Leon, J., Sakumi, K., Ide, T., Kang, D., LaFerla, F. M., & Nakabeppu, Y.
- Affiliations
- Kyushu University (JP)
- University of California, Irvine (US)
- Corresponding author
- Nakabeppu, Yusaku
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-11-29
- Volume
- 6
- Issue
- 1
- Pages
- 37889-37889
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5126576
- OpenAlex
- W2558650766
- Cited by
- 78
- References
- 57
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 13 · 2020: 8 · 2019: 12 · 2018: 6 · 2017: 3
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Japan Agency for Medical Research and Development (H25-ninchisho-ippann-004)
- Ministry of Health, Labour and Welfare (H20-ninchisho-ippan-004)
- Fakultet Medicinskih Nauka, Univerziteta U Kragujevcu
- Japan Society for the Promotion of Science (22221004, 15H04298, 15K15085, 25461281)
- 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, TFAM, amyloid-beta, mitochondrial dysfunction, oxidative stress, 8-oxoguanine, mitochondrial DNA damage, prealbumin, amyloid-beta aggregation, 3xTg-AD mice, iPSC-derived neurons, neurite outgrowth, cognitive function, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Cognition, Disease Models, Animal, DNA-Binding Proteins, DNA, Mitochondrial, Humans, Mice, Transgenic, Mitochondria, Prealbumin, Transcription Factors, Amyloid beta-Peptides, Reactive Oxygen Species, Oxidative Stress, Mitochondrial Proteins, Mice, Presenilin-1, Induced Pluripotent Stem Cells
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