{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:51:29Z","timestamp":1791312689469,"version":"4.3.1"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"41","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"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":[[2026,10,13]]},"abstract":"<jats:p>\n                    The mechanisms underlying type 2 diabetes\u2013associated cognitive dysfunction (DACD) remain poorly understood, hindering therapeutic progress. Here, we integrated spatial transcriptomics and single-nucleus RNA sequencing to delineate the spatiotemporal molecular and cellular landscape of DACD in brain tissues from 3- and 6-mo-old mouse models. Our findings revealed region- and cell-type-specific transcriptomic alterations, with excitatory neurons in the hippocampus and isocortex emerging as the most severely affected populations with pronounced synaptic dysfunction. Further analysis of these two regions identified disease-associated transcription factors, such as\n                    <jats:italic toggle=\"yes\">Rfx3<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Mef2c<\/jats:italic>\n                    . In parallel, we uncovered multiple ligand\u2013receptor pairs, including\n                    <jats:italic toggle=\"yes\">Hsp90b1<\/jats:italic>\n                    \u2013\n                    <jats:italic toggle=\"yes\">Lrp6<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">S100a1<\/jats:italic>\n                    \u2013\n                    <jats:italic toggle=\"yes\">Ryr2<\/jats:italic>\n                    , whose downstream signaling networks converged on lactate dehydrogenase B (\n                    <jats:italic toggle=\"yes\">Ldhb<\/jats:italic>\n                    ) as a shared effector, thereby prompting functional validation. Notably, brain-wide and excitatory neuron-specific\n                    <jats:italic toggle=\"yes\">Ldhb<\/jats:italic>\n                    overexpression alleviated DACD-induced mitochondrial dysfunction, oxidative stress, neuronal apoptosis, and cognitive impairment. Collectively, our study delineates the spatiotemporal transcriptomic landscape of DACD, offers a valuable resource for mechanistic exploration, and highlights\n                    <jats:italic toggle=\"yes\">Ldhb<\/jats:italic>\n                    as a potential therapeutic target in DACD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2529793123","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:04:38Z","timestamp":1791309878000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Spatial and single-nucleus transcriptomics reveals the molecular pathology of type 2 diabetes\u2013associated cognitive 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Ma Spatial and single-nucleus transcriptomics reveal the molecular pathology of type 2 diabetes-associated cognitive dysfunction and therapeutic potential of Ldhb. Genome Sequence Archive. https:\/\/ngdc.cncb.ac.cn\/gsa\/browse\/CRA020082. Deposited 14 October 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2529793123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:05:35Z","timestamp":1791309935000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2529793123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":35,"journal-issue":{"issue":"41","published-print":{"date-parts":[[2026,10,13]]}},"alternative-id":["10.1073\/pnas.2529793123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2529793123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]},"assertion":[{"value":"2025-10-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2529793123"}}