OPA1 Enhances Microglial Amyloid-β Clearance and Alleviates Cognitive Impairments in an Alzheimer's Disease Model.

Abstract

Amyloid deposition is thought to be a pathologic hallmark of Alzheimer disease (AD), which is associated with cognitive decline. Microglia play a crucial role in the pathology of AD, especially in the clearance of Aβ. Optic atrophy 1 (OPA1) is a GTPase primarily on the inner mitochondrial membrane, related to mitochondrial dynamics and cellular energy metabolism. Here, we found that decreased OPA1 expression and defective mitochondrial morphology in microglia during AD. Next, we utilized an OPA1 activator BGP-15, an OPA1 inhibitor myls22 and an OPA1 overexpression virus to investigate the role of OPA1 in AD. Our findings demonstrate that OPA1 promotes ATP production and Aβ clearance by microglia, leading to improved cognitive function. This may relate to down-regulation of hexokinase-2 (HK2) expression. These results suggest a critical role for OPA1 in Aβ clearance by microglia and a promising new direction for therapeutic approaches in AD.