Amyloid beta glycation leads to 1 neuronal mitochondrial dysfunction and Alzheimer’s pathogenesis through VDAC1-dependent mtDNA efflux

Abstract

Amyloid beta (Aβ), a stable protein, undergoes posttranslational glycation, forming glycated Aβ (gAβ), an advanced glycation end product (AGE) observed in Alzheimers' disease (AD), yet the pathological role of gAβ remains understudied. This work explores the role of gAβ in inducing neuronal mitochondrial DNA (mtDNA) efflux in a VDAC1-dependent manner and in activating the innate immune cGAS-STING pathway in AD. Findings demonstrate cGAS-mtDNA binding induced by gAβ in neuro-cytoplasm along with cGAS-STING activation in aged AD mice and human AD brains. Knockdown of RAGE, cGAS, or STING protects APP mice from mitochondrial dysfunction and AD-like pathology, as does inhibiting VDAC1. Moreover, RAGE inhibition in APP knock-in mice, coupled with spatially enhanced resolution omics-sequencing, confirms downregulation of innate immune responses and disease-associated genes in AD. Therefore, this study identifies a crucial link between gAβ and innate immunity, indicating therapeutic targeting of VDAC1, RAGE, or cGAS-STING may enhance resilience against gAβ-related pathological insults in AD.