ArticleProceedings of the National Academy of Sciences of the United States of America2025
Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Advanced glycation end products drive blood-brain barrier lipid dysregulation via RAGE-ABCA1 signaling to promote neurovascular dysfunction in Alzheimer's disease.Molecular psychiatry · 2026Article
- Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.Neural regeneration research · 2026Article
- The Secretome Derived From Human Umbilical Cord Mesenchymal Stem Cells Improves Skin Photoaging by Enhancing Mitophagy to Inhibit the cGAS-STING Pathway.Aging cell · 2026Article
- APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.Free radical biology & medicine · 2026Article
- The cGAS-STING pathway in inflammaging and neuroinflammation.Science China. Life sciences · 2026Review
- Diazonium-Enabled Post-Synthetic Construction of Enantiomeric Single-Atom Nanoagents Used for Alzheimer's Disease Treatment.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- α/Sulfonyl-γ-AApeptide foldamers mitigate Alzheimer's disease pathology by stabilizing transient helical domains in Aβ.Nature communications · 2026Article
- Viral Mimicry of Alzheimer's Disease: Innate Sensing of Self-Nucleic Acids as a Driver of Glial Senescence.Journal of molecular neuroscience : MN · 2026Review
- Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and associated diseases.Apoptosis : an international journal on programmed cell death · 2026Article
- APOE4 impairs Nrf2-PINK1/Parkin-dependent mitochondrial clearance through disrupted antioxidant and mitophagy signaling.Free radical biology & medicine · 2026Article
- Mitochondrial homeostasis and aging: the mtDNA-cGAS-STING axis.Frontiers in immunology · 2026Review
- The Microbiome-Mitochondria Axis in aging: a self-reinforcing vicious cycle linking metabolic dysregulation, mitochondrial quality control failure, and inflammaging.Frontiers in microbiology · 2026Review
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9 authors.
Funding
Abstract
Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ 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 Alzheimer's-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 gAβ-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 gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.
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