Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter <i>SLC13A5</i> and Citrate Metabolism Genes Across Alzheimer's Disease Pseudoprogression: A Single-Nucleus RNA Sequencing Analysis of the Human Middle Temporal Gyrus.
Overview
- Laboratório de Erros Inatos do Metabolismo, Programa de Bioquímica e Biofísica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-599, Brazil; (P.F.S.); (G.d.C.F.)
- Laboratório de Informática em Saúde (LabInfoS), Departamento de Ciências Médicas Integradas, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Cabo Frio 28905-320, Brazil
Abstract
The sodium-coupled citrate transporter NaCT (SLC13A5) imports extracellular citrate into cells. 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’s role in neurometabolic homeostasis, its transcriptional behavior across Alzheimer’s 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’s 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 < 0.001). The A1-reactive Astro 3 supertype, where SLC13A5 prevalence was 0.87%, declined concordantly (rho = −0.393). 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: −0.307 to −0.349, FDR < 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.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- portal.brain-map.org/
atlases-and-data/ , at Allen Brain Map; found in “Data Availability Statement”rnaseq
Data Availability Statement
The SEA-AD MTG dataset analyzed in this study is publicly available via the Allen Brain Cell Atlas at https://
Reproduced under the paper's license (CC BY), from the paper cited above.
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 10 keywords, 5 funders, 31 references.
Cite
This paper
Schuck, P. F., da Costa Ferreira, G., & Freitas, H. R. (2026). Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter &
BibTeX
@article{schuck2026astro
author = {Schuck, Patricia Fernanda and da Costa Ferreira, Gustavo and Freitas, Hércules Rezende},
title = {{Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter \&
journal = {Current issues in molecular biology},
year = {2026},
month = jul,
volume = {48},
number = {7},
pages = {691},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
issn = {1467-3037},
doi = {10.3390/
url = {https://
pmid = {42510931},
pmcid = {PMC13407191}
}
RIS
TY - JOUR
AU - Schuck, Patricia Fernanda
AU - da Costa Ferreira, Gustavo
AU - Freitas, Hércules Rezende
TI - Astrocyte Subtype-Specific Expression of the Sodium-Coupled Citrate Transporter &
T2 - Current issues in molecular biology
J2 - Curr Issues Mol Biol
PY - 2026
DA - 2026/
VL - 48
IS - 7
SP - 691
SN - 1467-3037
PB - Multidisciplinary Digital Publishing Institute (MDPI)
DO - 10.3390/
UR - https://
LA - en
ER -
CSL-JSON
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"language": "en",
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