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In the CNS, SLC13A5 is described to be expressed predominantly in neurons. Cytosolic citrate levels rely on citrate generated in mitochondria and imported from other CNS cells, regulating intermediary metabolism and supplying acetyl-CoA for lipid synthesis and histone acetylation. Despite evidence for NaCT\u2019s role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer\u2019s disease (AD) progression and across astrocyte subtypes remains uncharacterized at single-cell resolution. We analyzed single-nucleus RNA sequencing data from 1,378,211 nuclei across 84 donors in the Seattle Alzheimer\u2019s Disease Brain Cell Atlas (SEA-AD) Middle Temporal Gyrus dataset to profile SLC13A5 and seven citrate metabolism genes across a continuous AD pseudoprogression score. SLC13A5 expression was restricted to astrocytes (~20% prevalence) and concentrated in the Astro 2 supertype (24.0%), a homeostatic subtype characterized by low C3 (1.6%) and CD44 (5.5%), which expanded with pseudoprogression (Spearman rho = +0.345, FDR &lt; 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = \u22120.393). Opposing compositional and transcriptional forces produced apparent stability in overall SLC13A5 prevalence. SLC13A3 and ACO1 showed progressive donor-level declines correlating with Braak stage and Thal phase (rho range: \u22120.307 to \u22120.349, FDR &lt; 0.01). APOE4 carriers exhibited lower SLC13A5 prevalence specifically within Astro 2 nuclei (median 17.6% vs. 25.9%; Wilcoxon p = 0.025), though this association did not survive multivariate regression. No difference in Astro 2 SLC13A5 expression was detected between cognitively resilient and expected-AD donors with equivalent high Braak burden (p = 0.888). Contrary to the prevailing description of NaCT as a neuronal transporter, SLC13A5 transcript in the SEA-AD MTG dataset was detected almost exclusively in astrocyte nuclei, concentrated in the homeostatic Astro 2 subtype, and maintained as this subtype expanded with advancing AD pathology. Because these are nuclear transcript measurements, they delimit where SLC13A5 mRNA is detectable rather than establishing the cellular site of NaCT protein or activity, which requires in situ validation.<\/jats:p>","DOI":"10.3390\/cimb48070691","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:01:08Z","timestamp":1783346468000},"page":"691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter SLC13A5 and Citrate Metabolism Genes Across Alzheimer\u2019s Disease Pseudoprogression: A Single-Nucleus RNA Sequencing Analysis of the Human Middle Temporal Gyrus"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3148-4952","authenticated-orcid":false,"given":"Patricia Fernanda","family":"Schuck","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Erros Inatos do Metabolismo, Programa de Bioqu\u00edmica e Biof\u00edsica Celular, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-599, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-8842","authenticated-orcid":false,"given":"Gustavo","family":"da Costa Ferreira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Erros Inatos do Metabolismo, Programa de Bioqu\u00edmica e Biof\u00edsica Celular, Instituto de Bioqu\u00edmica M\u00e9dica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-599, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1584-9157","authenticated-orcid":false,"given":"H\u00e9rcules Rezende","family":"Freitas","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Inform\u00e1tica em Sa\u00fade (LabInfoS), Departamento de Ci\u00eancias M\u00e9dicas Integradas, Faculdade de Ci\u00eancias M\u00e9dicas, Universidade do Estado do Rio de Janeiro, Cabo Frio 28905-320, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"39469","DOI":"10.1074\/jbc.M207072200","article-title":"Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain","volume":"277","author":"Inoue","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1126\/science.1164097","article-title":"ATP-citrate lyase links cellular metabolism to histone acetylation","volume":"324","author":"Wellen","year":"2009","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ajhg.2014.06.006","article-title":"Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life","volume":"95","author":"Thevenon","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.1093\/brain\/awv263","article-title":"Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia","volume":"138","author":"Hardies","year":"2015","journal-title":"Brain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1126\/science.290.5499.2137","article-title":"Extended life-span conferred by cotransporter gene mutations in Drosophila","volume":"290","author":"Rogina","year":"2000","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.cmet.2011.06.009","article-title":"Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance","volume":"14","author":"Birkenfeld","year":"2011","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1152\/physrev.00042.2016","article-title":"Physiology of astroglia","volume":"98","author":"Verkhratsky","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00401-009-0619-8","article-title":"Astrocytes: Biology and pathology","volume":"119","author":"Sofroniew","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","article-title":"Single-cell transcriptomic analysis of Alzheimer\u2019s disease","volume":"570","author":"Mathys","year":"2019","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41593-020-0624-8","article-title":"Disease-associated astrocytes in Alzheimer\u2019s disease and aging","volume":"23","author":"Habib","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/s41593-020-00783-4","article-title":"Reactive astrocyte nomenclature, definitions, and future directions","volume":"24","author":"Escartin","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ferreira, B.K., Schuck, P.F., Ferreira, G.C., and Freitas, H.R. (2026). Potential biological processes related to brain SLC13A5 across the lifespan: Weighted gene co-expression network analysis from large human transcriptomic data. Brain Sci., 16.","DOI":"10.20944\/preprints202601.0041.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1038\/s41593-024-01774-5","article-title":"Integrated multimodal cell atlas of Alzheimer\u2019s disease","volume":"27","author":"Gabitto","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of A\u03b2-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2019s disease","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"ref_18","unstructured":"Fischer, B., Smith, M., and Pau, G. (2025). rhdf5: R Interface to HDF5, CRAN. Available online: https:\/\/github.com\/Huber-group-EMBL\/rhdf5."},{"key":"ref_19","first-page":"20","article-title":"segmented: An R package to fit regression models with broken-line relationships","volume":"8","author":"Muggeo","year":"2008","journal-title":"R News"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.neuron.2018.05.008","article-title":"APOE4 causes widespread molecular and cellular alterations associated with Alzheimer\u2019s disease phenotypes in human iPSC-derived brain cell types","volume":"98","author":"Lin","year":"2018","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/S1474-4422(12)70191-6","article-title":"Cognitive reserve in ageing and Alzheimer\u2019s disease","volume":"11","author":"Stern","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_22","unstructured":"R Core Team (2026). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_24","unstructured":"Bates, D., Maechler, M., and Jagan, M. (2026). Matrix: Sparse and Dense Matrix Classes and Methods, CRAN. R package version 1.7-5."},{"key":"ref_25","unstructured":"Robinson, D., Hayes, A., Couch, S., and Hvitfeldt, E. (2026). broom: Convert Statistical Objects into Tidy Tibbles, CRAN. R package version 1.0.13."},{"key":"ref_26","unstructured":"Fox, J., and Weisberg, S. (2019). An R Companion to Applied Regression, Sage. [3rd ed.]. Available online: https:\/\/www.john-fox.ca\/Companion\/."},{"key":"ref_27","unstructured":"Lin Pedersen, T. (2025). patchwork: The Composer of Plots, CRAN. R package version 1.3.2."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2016). ggplot2: Elegant Graphics for Data Analysis, Springer. Available online: https:\/\/ggplot2.tidyverse.org.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"ref_29","unstructured":"Wickham, H., Lin Pedersen, T., and Seidel, D. (2025). scales: Scale Functions for Visualization, CRAN. R package version 1.4.0."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ramos, M.C., da C\u00e2mara, A.O., and Freitas, H.R. (2026). From Pipettes to p-Values: A Framework for Companion Statistical Reporting in Experimental Neuroscience. Standards, 6.","DOI":"10.3390\/standards6020013"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5779","DOI":"10.1074\/jbc.270.11.5779","article-title":"Sequence and functional characterization of a renal sodium\/dicarboxylate cotransporter","volume":"270","author":"Pajor","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41591-019-0695-9","article-title":"Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer\u2019s disease","volume":"26","author":"Zhou","year":"2020","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1038\/s41593-019-0539-4","article-title":"A single-cell atlas of entorhinal cortex from individuals with Alzheimer\u2019s disease reveals cell-type-specific gene expression regulation","volume":"22","author":"Grubman","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/nchembio807","article-title":"The role of iron regulatory proteins in mammalian iron homeostasis and disease","volume":"2","author":"Rouault","year":"2006","journal-title":"Nat. Chem. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1016\/j.cell.2022.05.017","article-title":"Cholesterol and matrisome pathways dysregulated in astrocytes and microglia","volume":"185","author":"Tcw","year":"2022","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.neuron.2013.10.036","article-title":"The central dogma decentralized: New perspectives on RNA function and local translation in neurons","volume":"80","author":"Holt","year":"2013","journal-title":"Neuron"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/691\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:15:00Z","timestamp":1783656900000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/691"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,5]]},"references-count":36,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cimb48070691"],"URL":"https:\/\/doi.org\/10.3390\/cimb48070691","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,5]]}}}