Spatial and single-nucleus transcriptomics reveals the molecular pathology of type 2 diabetes–associated cognitive dysfunction

The mechanisms underlying type 2 diabetes–associated 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 Rfx3 and Mef2c . In parallel, we uncovered multiple ligand–receptor pairs, including Hsp90b1 – Lrp6 and S100a1 – Ryr2 , whose downstream signaling networks converged on lactate dehydrogenase B ( Ldhb ) as a shared effector, thereby prompting functional validation. Notably, brain-wide and excitatory neuron-specific Ldhb 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 Ldhb as a potential therapeutic target in DACD.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-10-06
DOI
https://doi.org/10.1073/pnas.2529793123
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
0.00
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article

Spatial and single-nucleus transcriptomics reveals the molecular pathology of type 2 diabetes–associated cognitive dysfunction

Shengbao Suo, Gholson J. Lyon, Ning‐Yi Shao, Yaqing Shu et al.
Proceedings of the National Academy of Sciences
Single-cell and spatial transcriptomics
article

Spatial and single-nucleus transcriptomics reveals the molecular pathology of type 2 diabetes–associated cognitive dysfunction

Shengbao Suo, Gholson J. Lyon, Ning‐Yi Shao, Yaqing Shu, Baojian Liao, Siyu Kong, Yumeng Yang, Ning Ma, Bingbing Xie, Xixi Zhang, Yanping Lu, Wei Wu, Lei Zhang, Xiu Liang, Mingyue Jiang, Xiaojing Zhang, Meiyi Zhou
article en

Abstract

The mechanisms underlying type 2 diabetes–associated 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 Rfx3 and Mef2c . In parallel, we uncovered multiple ligand–receptor pairs, including Hsp90b1 – Lrp6 and S100a1 – Ryr2 , whose downstream signaling networks converged on lactate dehydrogenase B ( Ldhb ) as a shared effector, thereby prompting functional validation. Notably, brain-wide and excitatory neuron-specific Ldhb 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 Ldhb as a potential therapeutic target in DACD.

Proceedings of the National Academy of SciencesVol. 123(41)
Sun Yat-sen University (CN), Yunnan University (CN), University of Macau (MO), First Affiliated Hospital of Guangzhou Medical University (CN), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN), The Third Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine (CN), Guangdong Academy of Medical Sciences (CN), Sun Yat-sen University Cancer Center (CN), Third Affiliated Hospital of Sun Yat-sen University (CN), Guangdong Provincial People's Hospital (CN), State Key Laboratory of Respiratory Disease (CN), State Key Laboratory of Oncology in South China, Guangzhou Laboratory, Southern Medical University (CN), Guangzhou Medical University (CN)
Openalex Percentile: Top 21%
Single-cell and spatial transcriptomics
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