Amyloid Beta Glycation Induces Neuronal Mitochondrial Dysfunction and Alzheimers Pathogenesis via VDAC1-Dependent mtDNA Efflux

Abstract

Glycation, the non-enzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimers disease (AD), amyloid-beta (A{beta}) undergoes post-translational glycation to produce glycated A{beta} (gA{beta}), yet its pathological role remains poorly understood. Here, we demonstrate that gA{beta} promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimers-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gA{beta}-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gA{beta} and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD. Significance StatementThis study reveals how a modified form of amyloid-beta disrupts mitochondrial function in neurons, triggering innate immunity and disease progression. We show that this modified amyloid-beta damages mitochondria, activating a specific immune response in the brain. By identifying the key molecules involved, we provide potential targets for new Alzheimers treatments aimed at preventing mitochondrial damage and cognitive decline. This research offers fresh insights into Alzheimers development and highlights new therapeutic pathways.