Amyloid beta glycation leads to neuronal mitochondrial dysfunction and Alzheimers pathogenesis through VDAC1-dependent mtDNA efflux
Amyloid beta (A{beta}), a stable protein, undergoes posttranslational glycation, forming glycated A{beta} (gA{beta}), an advanced glycation end product (AGE) observed in Alzheimers' disease (AD), yet the pathological role of gA{beta} remains understudied. This work explores the role of gA{beta} 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 gA{beta} 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 gA{beta} and innate immunity, indicating therapeutic targeting of VDAC1, RAGE, or cGAS-STING may enhance resilience against gA{beta}-related pathological insults in AD.