Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease
Abstract Background Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer’s disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurit...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-024-00702-2 |
| _version_ | 1797349723933245440 |
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| author | Maria Calvo-Rodriguez Elizabeth K. Kharitonova Austin C. Snyder Steven S. Hou Maria Virtudes Sanchez-Mico Sudeshna Das Zhanyun Fan Hamid Shirani K. Peter R. Nilsson Alberto Serrano-Pozo Brian J. Bacskai |
| author_facet | Maria Calvo-Rodriguez Elizabeth K. Kharitonova Austin C. Snyder Steven S. Hou Maria Virtudes Sanchez-Mico Sudeshna Das Zhanyun Fan Hamid Shirani K. Peter R. Nilsson Alberto Serrano-Pozo Brian J. Bacskai |
| author_sort | Maria Calvo-Rodriguez |
| collection | DOAJ |
| description | Abstract Background Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer’s disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants. Methods We expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques. Results For the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aβ plaque burden. Conclusions Considering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD. |
| first_indexed | 2024-03-08T12:34:31Z |
| format | Article |
| id | doaj.art-831a14a43be94b0caad5a381475bab71 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-03-08T12:34:31Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-831a14a43be94b0caad5a381475bab712024-01-21T12:35:20ZengBMCMolecular Neurodegeneration1750-13262024-01-0119111810.1186/s13024-024-00702-2Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s diseaseMaria Calvo-Rodriguez0Elizabeth K. Kharitonova1Austin C. Snyder2Steven S. Hou3Maria Virtudes Sanchez-Mico4Sudeshna Das5Zhanyun Fan6Hamid Shirani7K. Peter R. Nilsson8Alberto Serrano-Pozo9Brian J. Bacskai10Department of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Physics, Chemistry and Biology, Linköping UniversityDepartment of Physics, Chemistry and Biology, Linköping UniversityDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurology, Massachusetts General Hospital and Harvard Medical SchoolAbstract Background Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer’s disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants. Methods We expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques. Results For the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aβ plaque burden. Conclusions Considering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.https://doi.org/10.1186/s13024-024-00702-2Oxidative stressROSAlzheimer’s diseaseMitochondriaSS31Neurodegeneration |
| spellingShingle | Maria Calvo-Rodriguez Elizabeth K. Kharitonova Austin C. Snyder Steven S. Hou Maria Virtudes Sanchez-Mico Sudeshna Das Zhanyun Fan Hamid Shirani K. Peter R. Nilsson Alberto Serrano-Pozo Brian J. Bacskai Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease Molecular Neurodegeneration Oxidative stress ROS Alzheimer’s disease Mitochondria SS31 Neurodegeneration |
| title | Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease |
| title_full | Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease |
| title_fullStr | Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease |
| title_full_unstemmed | Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease |
| title_short | Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease |
| title_sort | real time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of alzheimer s disease |
| topic | Oxidative stress ROS Alzheimer’s disease Mitochondria SS31 Neurodegeneration |
| url | https://doi.org/10.1186/s13024-024-00702-2 |
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