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Cited by 20Alzheimer's disease research and treatmentsMitochondrial Function and PathologyAutophagy in Disease and Therapy

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Mitochondrial vulnerability to oxidation in human brain organoids modelling Alzheimer's disease

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Holubiec, Mariana I., Alloatti, Matias, Bianchelli, Julieta, Greloni, Francisco, Arnaiz, Cayetana, Gonzalez Prinz, Melina, Fernandez Bessone, Ivan, Pozo Devoto, Victorio, Falzone, Tomas L.·2023·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2023.08.028
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Abstract

Reactive Oxygen Species (ROS) and mitochondrial dysfunction are implicated in the pathogenesis of Alzheimer's disease (AD), a common neurodegenerative disorder characterized by abnormal metabolism of the amyloid precursor protein (APP) in brain tissue. However, the exact mechanism by which abnormal APP leads to oxidative distress remains unclear. Damage to mitochondrial membrane and inhibition of mitochondrial respiration are thought to contribute to the progression of the disease. However, the lack of suitable human models that replicate pathological features, together with impaired cellular pathways, constitutes a major challenge in AD studies. In this work, we induced pluripotency in patient-derived skin fibroblasts carrying the Swedish mutation in App (APP swe ), to generate human brain organoids that model AD, and studied redox regulation and mitochondrial homeostasis. We found time-dependent increases in AD-related pathological hallmarks in APP swe brain organoids, including elevated Aβ levels, increased extracellular amyloid deposits, and enhanced tau phosphorylation. Interestingly, using live-imaging spinning-disk confocal microscopy, we found an increase in mitochondrial fragmentation and a significant loss of mitochondrial membrane potential in APP swe brain organoids when subjected to oxidative conditions. Moreover, ratiometric dyes in a live imaging setting revealed a selective increase in mitochondrial superoxide anion and hydrogen peroxide levels in APP swe brai…

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  • Amyloid peptides drive mitochondrial stress and NLRP3 inflammasome activation; tau pathology impairs synaptic plasticity and autophagic clearance; mitochondrial dysfunction produces ROS that promote amyloidogenic APP processing; and chronic glial activation sustains both amyloid and tau pathology.

    “Moreover, amyloid peptides drive mitochondrial stress and NLRP3 inflammasome activation, tau pathology impairs synaptic plasticity and autophagic clearance, mitochondrial dysfunction produces ROS that promote amyloidogenic APP processing, and chronic glial activation sustains both amyloid and tau pathology [169, 170].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [169]

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Metadata

Authors
Holubiec, M. I., Alloatti, M., Bianchelli, J., Greloni, F., Arnaiz, C., Gonzalez Prinz, M., Fernandez Bessone, I., Pozo Devoto, V., & Falzone, T. L.
Affiliations
  • Max Planck Society (DE)
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2023-11
Volume
208
Pages
394-401
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2023.08.028
OpenAlex
W4386296103
Cited by
20
References
8
Citations by year
2026: 4 · 2025: 12 · 2024: 3 · 2023: 1
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Conicet (publishedVersion, cc-by-nc-sa)
Funders
  • Agencia Nacional de Promoción de la Investigación el Desarrollo Tecnológico y la Innovación (PICT 2017\u20131648, PICT 2019-0217)
  • Agencia Nacional de Promoción Científica y Tecnológica
  • Consejo Nacional de Investigaciones Científicas y Técnicas (PUE Institucional IBCN 2018)
  • Universidad de Buenos Aires (UBACyT 2017/2019)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
Alzheimer's disease, brain organoids, APP Swedish mutation, amyloid-beta, tau phosphorylation, mitochondrial fragmentation, mitochondrial membrane potential, reactive oxygen species, mitochondrial superoxide, hydrogen peroxide, redox regulation, mitochondrial dysfunction, oxidative stress, induced pluripotent stem cells, dermal fibroblasts, mitochondrial homeostasis
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Mice, Transgenic, Mitochondria, Organoids, Oxidation-Reduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice

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