{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:50:34Z","timestamp":1793116234215,"version":"4.5.0"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"47","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,25]]},"abstract":"<jats:p>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\u2019s disease (AD), amyloid-beta (A\u03b2) undergoes posttranslational glycation to produce glycated A\u03b2 (gA\u03b2), yet its pathological role remains poorly understood. Here, we demonstrate that gA\u03b2 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\u2019s-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\u03b2-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\u03b2 and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.<\/jats:p>","DOI":"10.1073\/pnas.2505046122","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T20:00:32Z","timestamp":1763409632000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer\u2019s pathogenesis via VDAC1-dependent mtDNA efflux"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8836-601X","authenticated-orcid":false,"given":"Firoz","family":"Akhter","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Stony Brook University","place":["Stony Brook"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma","family":"Akhter","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Stony Brook University","place":["Stony Brook"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2092-6508","authenticated-orcid":false,"given":"Xiongwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University","place":["Cleveland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hillary","family":"Schiff","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, Stony Brook University","place":["Stony Brook"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Maffei","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, Stony Brook University","place":["Stony Brook"]},{"name":"Department of Neurobiology and Behavior, Neuroscience Graduate Program, Renaissance School of Medicine, Stony Brook University","place":["Stony Brook"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7901-184X","authenticated-orcid":false,"given":"Justin T.","family":"Douglas","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Nuclear Magnetic Resonance Core Laboratory, University of Kansas","place":["Lawrence"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qifa","family":"Zhou","sequence":"additional","affiliation":[{"name":"Alfred E. Mann Department of Biomedical Engineering, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8967-5570","authenticated-orcid":false,"given":"Zhen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3057-1889","authenticated-orcid":false,"given":"Donghui","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Stony Brook University","place":["Stony Brook"]},{"name":"Department of Neurobiology and Behavior, Neuroscience Graduate Program, Renaissance School of Medicine, Stony Brook University","place":["Stony Brook"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae229"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(96)00016-1"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0795-693"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.12.5710"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhh123"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/382685a0"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2009.04.016"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0718-3"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200114002"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-022-00337-2"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-022-00879-6"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-0986-1"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201949799"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.10.028"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2017.06.007"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav4011"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.152.2.237"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401950"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2010.10.010"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2006.03.016"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.002275"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102664108"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806192105"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1469-06.2006"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00524-z"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2008.57"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905686106"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401231"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008050514"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.627837"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao6047"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.09.020"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201439366"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402066"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad432"},{"key":"e_1_3_4_36_2","first-page":"1869","article-title":"Bax-inhibiting peptide attenuates bleomycin-induced lung injury in mice","volume":"6","author":"Suzuki K.","year":"2017","unstructured":"K. Suzuki , Bax-inhibiting peptide attenuates bleomycin-induced lung injury in mice. Biol Open 6, 1869\u20131875 (2017).","journal-title":"Biol Open"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05846-5"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-015-0263-6"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.06.007"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-191236"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.006846"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107282"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwu057"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06373-1"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12640"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1553-0"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2021.06.024"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00923-9"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1998.2580729.x"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2505046122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T20:01:08Z","timestamp":1763409668000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2505046122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":49,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2025,11,25]]}},"alternative-id":["10.1073\/pnas.2505046122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2505046122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]},"assertion":[{"value":"2025-03-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2505046122"}}