Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation
Open Access
- 12 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Communications Biology
- Vol. 4 (1), 1-13
- https://doi.org/10.1038/s42003-021-01720-2
Abstract
Mitochondrial pathophysiology is implicated in the development of Alzheimer’s disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related Aβ pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of Aβ fibrils, but not the spontaneous formation of Aβ fibrils and plaques, leading to excessive secondary generation of toxic and dispersible Aβ oligomers. Consistent with this, MITOL-deficient mice with Aβ etiology exhibited worsening cognitive decline depending on Aβ oligomers rather than Aβ plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of Aβ form, oligomers or plaques, responsible for disease development.Funding Information
- MEXT | Japan Society for the Promotion of Science (18H04869, 20H04911)
- Ministry of Education, Culture, Sports, Science and Technology (S1411014)
- Japan Agency for Medical Research and Development (17gm5010002, 18gm5010002, 19gm5010002 and 20gm5010002)
- Uehara Memorial Foundation (N/A)
- Naito Foundation (N/A)
- Takeda Medical Research Foundation (N/A)
- Sumitomo Foundation (N/A)
- Cosmetology Research Foundation (N/A)
- Ono Medical Research Foundation (N/A)
- Tokyo Biochemical Research Foundation (N/A)
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