Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.

The perturbed structure and function of mitochondria-associated membranes (MAM), instead of the amyloid cascade, have been gradually proposed to play a basic role in the pathogenesis of Alzheimer's disease (AD). Notably, autophagy inhibition is one of the main mechanisms of MAM dysfunction and plays an important role in neuronal injury. However, the upstream molecular mechanism underlying the MAM dysfunctions remains elusive. Here, we defined an unexpected and critical role of connexin43 (Cx43) in regulating the MAM structure. The expression levels of Cx43 and mitofusin-2 (MFN2, the MAM biomarker) increase significantly in 9-month-old APP(swe)/PS1(dE9) double-transgenic AD model mice, and there is an obvious colocalization relationship. Moreover, both AD mice and cells lacking Cx43 exhibit an evident reduction in the MAM contact sites, which subsequently promotes the conversion from microtubule-associated protein 1 light-chain 3B I (LC3B-I) to LC3B-II via inhibition mTOR-dependent pathway and then initiates the generation of autophagosomes. Autophagosome formation ultimately promotes β-amyloid (Aβ) clearance and attenuates Aβ-associated pathological changes in AD, mainly including astrogliosis and neuronal apoptosis. Our findings not only reveal a previously unrecognized effect of Cx43 on MAM upregulation but also highlight the major player of MAM-induced autophagy inhibition in Cx43-facilitated AD pathogenesis, providing a novel insight into the alternative therapeutic strategies for the early treatment of AD.