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Cited by 135Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Oxidative stress and altered mitochondrial protein expression in the absence of amyloid-β and tau pathology in iPSC-derived neurons from sporadic Alzheimer's disease patients

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Birnbaum, Julian H., Wanner, Debora, Gietl, Anton F., Saake, Antje, Kündig, Thomas M., Hock, Christoph, Nitsch, Roger M., Tackenberg, Christian·2018·Stem Cell Research
DOI 10.1016/j.scr.2018.01.019
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Abstract

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and increased production of reactive oxygen species (ROS) has been described in postmortem brain samples and animal models. However, these observations were made at a late stage of disease and the inability to examine an early, presymptomatic phase in human neurons impeded our understanding of cause or consequence of mitochondrial dysfunction in AD. We used human induced pluripotent stem cell-derived neuronal cells (iN cells) from sporadic AD (SAD) patients and healthy control subjects (HCS) to show aberrant mitochondrial function in patient-derived cells. We observed that neuronal cultures from some patients produced more ROS and displayed higher levels of DNA damage. Furthermore, patient-derived cells showed increased levels of oxidative phosphorylation chain complexes, whereas mitochondrial fission and fusion proteins were not affected. Surprisingly, these effects neither correlated with Aβ nor phosphorylated and total tau levels. Synaptic protein levels were also unaffected in SAD iN cells. The results of this study give new insights into constitutional metabolic changes in neurons from subjects prone to develop Alzheimer's pathology. They suggest that increased ROS production may have an integral role in the development of sporadic AD prior to the appearance of amyloid and tau pathology.

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Crossref · 10.1016/j.scr.2018.01.019

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  • Earlier studies showed increased oxidative stress mechanisms and ROS production as well as upregulation of mitochondrial respiratory complexes in iPSC-derived neurons from sporadic AD patients, even in the absence of changes in Aβ or tau and p-tau levels.

    “This aligns with earlier studies showing increased oxidative stress mechanisms and ROS production as well as upregulation of mitochondrial respiratory complexes in iPSC-derived neurons from sporadic AD patients, even in the absence of changes in Aβ or tau and p-tau levels [14].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [14]

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  • Human iN cell fusion and fission are stable mechanisms that are not affected by other mitochondrial dysfunctions.

    “This is in agreement with a previous study showing altered levels of ETC complexes in iN cells from AD patients in the absence of fusion and fission alterations [14], suggesting that human iN cell fusion and fission are stable mechanisms that are not affected by other mitochondrial dysfunctions.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [14]

    The Results report altered oxidative phosphorylation complex composition without changes in most measured fusion and fission markers in the AD patient-derived iN cells. They also report lower OPA1 mRNA in one patient cell line. These observations do not establish that fusion and fission are generally stable mechanisms unaffected by other mitochondrial dysfunctions. (LLM, conf=0.86)

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  • A previous study showed altered levels of ETC complexes in iN cells from AD patients in the absence of fusion and fission alterations.

    “This is in agreement with a previous study showing altered levels of ETC complexes in iN cells from AD patients in the absence of fusion and fission alterations [14], suggesting that human iN cell fusion and fission are stable mechanisms that are not affected by other mitochondrial dysfunctions.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [14]

    The Results (Fig. 3) report altered oxidative-phosphorylation complex subunit levels in AD-derived iN cells and generally unchanged levels of the fusion and fission markers examined. However, they also report lower OPA1 mRNA, a fusion marker, in AD2 cells. Thus the claim's unqualified absence of fusion alterations omits an exception. (LLM, conf=0.88)

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Research works printed but not linked: 2

  1. Rhein, V., Song, X., Wiesner, A., Ittner, L.M., Baysang, G., Meier, F., Ozmen, L., Bluethmann, H., Drose, S., Brandt, U., Savaskan, E., Czech, C., Gotz, J., Eckert, A., 2009. Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple trans- genic Alzheimer's disease mice. Proc. Natl. Acad. Sci. U. S. A. 106, 20057-20062.
  2. Yao, J., Irwin, R.W., Zhao, L., Nilsen, J., Hamilton, R.T., Brinton, R.D., 2009. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 106, 14670-14675.

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Authors
Birnbaum, J. H., Wanner, D., Gietl, A. F., Saake, A., Kündig, T. M., Hock, C., Nitsch, R. M., & Tackenberg, C.
Affiliations
  • University of Zurich (CH)
  • University Hospital Zurich (CH)
Corresponding author
Tackenberg, Christian
ORCID
Venue
Stem Cell Research
Publisher
Elsevier BV
Published
2018-03
Volume
27
Pages
121-130
ISSN
1873-5061 (ISSN-L)
DOI
10.1016/j.scr.2018.01.019
OpenAlex
W2789861219
Cited by
135
References
12
Citations by year
2026: 8 · 2025: 11 · 2024: 15 · 2023: 12 · 2022: 17 · 2021: 30 · 2020: 23 · 2019: 14 · 2018: 5
FWCI
11.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • Novartis Foundation for medical-biological research (14C176)
  • UZH Forschungskredit (FK-15-023)
  • Olga Mayenfisch Foundation
  • Mäxi Foundation
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
sporadic Alzheimer's disease, mitochondrial dysfunction, oxidative stress, reactive oxygen species, iPSC-derived neurons, mitochondrial protein expression, DNA damage, amyloid-beta, tau phosphorylation, mitochondrial fission and fusion, preclinical Alzheimer's disease, synaptic proteins
MeSH terms
Alzheimer Disease, Cell Line, Cells, Cultured, DNA Damage, Humans, Mitochondria, Neurons, Amyloid beta-Peptides, tau Proteins, Reactive Oxygen Species, Oxidative Stress

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