Mitochondrial ubiquitin ligase alleviates Alzheimer's disease pathology via blocking the toxic amyloid-? oligomer generation.

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 A? pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of A? fibrils, but not the spontaneous formation of A? fibrils and plaques, leading to excessive secondary generation of toxic and dispersible A? oligomers. Consistent with this, MITOL-deficient mice with A? etiology exhibited worsening cognitive decline depending on A? oligomers rather than A? plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of A? form, oligomers or plaques, responsible for disease development.

SUBMITTER: Takeda K 

PROVIDER: S-EPMC7881000 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature