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Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer’s Disease Decreases Amyloid Beta Plaque Formation

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Abstract

For decades, mitochondrial dysfunctions and the generation of reactive oxygen species have been proposed to promote the development and progression of the amyloid pathology in Alzheimer’s disease, but this association is still debated. It is unclear whether different mitochondrial dysfunctions, such as oxidative phosphorylation deficiency and oxidative stress, are triggers or rather consequences of the formation of amyloid aggregates. Likewise, the role of the different mitochondrial oxidative phosphorylation complexes in Alzheimer’s patients’ brain remains poorly understood. Previous studies showed that genetic ablation of oxidative phosphorylation enzymes from early age decreased amyloid pathology, which were unexpected results. To better model oxidative phosphorylation defects in aging, we induced the ablation of mitochondrial Complex III (CIIIKO) in forebrain neurons of adult mice with amyloid pathology. We found that mitochondrial Complex III dysfunction in adult neurons induced mild oxidative stress but did not increase amyloid beta accumulation. On the contrary, CIIIKO-AD mice showed decreased plaque number, decreased Aβ42 toxic fragment, and altered amyloid precursor protein clearance pathway. Our results support the hypothesis that mitochondrial dysfunctions alone, caused by oxidative phosphorylation deficiency, is not the cause of amyloid accumulation.

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Data Availability

The complete datasets used and/or analyzed during the current study are available from the corresponding author on request.

Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer’s disease

APP/PS1:

Amyloid precursor protein (Mo/HuAPP695swe), presenilin 1 (PS1-dE9)

ATP5a:

ATP synthase alpha-subunit gene

BACE1:

Beta-secretase 1, beta-site APP cleaving enzyme 1

BN-PAGE:

Blue native polyacrylamide gel electrophoresis

CaMKIIα:

Calcium/calmodulin-dependent protein kinase II alpha

COX1:

Cyclooxygenase 1 (cytochrome c oxidase)

CS:

Citrate synthase

CTF:

APP C-terminal fragment

CytC:

Cytochrome C

GFAP:

Glial fibrillary acidic protein

Iba1:

Ionized calcium binding adaptor molecule 1

LC3B:

Autophagy marker light chain 3

mtDNA:

Mitochondrial DNA

NDUFB8:

NADH:ubiquinone oxidoreductase subunit B8

NDUFA9:

NADH:ubiquinone oxidoreductase subunit A9

OXPHOS:

Oxidative phosphorylation

PBS:

Phosphate-buffered saline

PFA:

Paraformaldehyde

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PVDF:

Polyvinylidene difluoride

RISP:

Rieske iron sulfur protein

ROS:

Reactive oxygen species

RT:

Room temperature

SDHA:

Succinate dehydrogenase complex dlavoprotein subunit A

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SOD2:

Superoxide dismutase 2

TUJ1:

Neuron-specific class III beta-tubulin

UQCRC1/Core1:

Ubiquinol-cytochrome C reductase core protein 1

UQCRFS1:

Ubiquinol-cytochrome C reductase, Rieske iron-sulfur polypeptide 1

VDAC1/Porin:

Voltage-dependent anion channel

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Funding

This work was supported primarily by the Florida Biomedical Foundation Ed and Ethel Moore Alzheimer’s Disease Research Program grant 5AZ06 (CTM), the National Institute of Health Grants K01AG057815 (MP), and 1R01NS079965 (CTM). The following grants also helped support this work: NIH grants 5R01EY010804, 1R01AG036871, R33ES025673, and the Muscular Dystrophy Association.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

    Milena Pinto, Francisca Diaz, Nadee Nissanka & Carlos T. Moraes

  2. The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Chelsey S. Guastucci, Placido Illiano & Roberta Brambilla

Authors
  1. Milena Pinto
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  2. Francisca Diaz
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  3. Nadee Nissanka
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  4. Chelsey S. Guastucci
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  5. Placido Illiano
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  6. Roberta Brambilla
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  7. Carlos T. Moraes
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Contributions

MP designed the research, performed the experiments, analyzed, and interpreted data, and wrote the manuscript. FD performed BN-PAGE analysis, enzymatic activity, and contributed intellectually to the research. NN performed qPCR analysis. CSG and PI assisted in plaque counting. RB contributed intellectually to the research. CTM planned the project together with MP and contributed to the writing of the manuscript. All authors read and approved the final manuscript. Francisca Diaz and Placido Illiano passed away before the submission of the manuscript.

Corresponding authors

Correspondence to Milena Pinto or Carlos T. Moraes.

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All experiments and animal husbandry were performed according to a protocol approved by the University of Miami Institutional Animal Care and Use Committee.

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The authors have no relevant financial or non-financial interests to disclose.

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Francisca Diaz deceased in March 2021.

Placido Illiano deceased in February 2022.

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Pinto, M., Diaz, F., Nissanka, N. et al. Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer’s Disease Decreases Amyloid Beta Plaque Formation. Mol Neurobiol 59, 6552–6566 (2022). https://doi.org/10.1007/s12035-022-02992-3

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