Mitochondrial ubiquitin ligase alleviates Alzheimer\u2019s disease pathology via blocking the toxic amyloid-\u03b2 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 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.