Single-nucleus transcriptomics uncovers region-specific molecular features underlying selective aging vulnerability of cholinergic neurons.

Qianqian Li, Jiale Chen, Xiuli Liu, Hui Gong, Xiangning Li, Miao Ren

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Article in iScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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6 authors.

Qianqian LiWuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China.

Jiale ChenDepartment of Medical 3D Printing Center, The First Affiliated Hospital of Soochow University, Suzhou 215000, China.

Xiuli LiuWuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China.

Hui GongWuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China.

Xiangning LiState Key Laboratory of Digital Medical Engineering, Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570100, China.

Miao RenState Key Laboratory of Digital Medical Engineering, Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570100, China.

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6 · The paper itself

Abstract

Cholinergic neurons exhibit functional and molecular heterogeneity across the basal forebrain (BF), midbrain (MB), and brainstem (BS), while the aging-associated transcriptional features remain poorly characterized. Here, we performed single nucleus RNA sequencing (snRNA-seq) on 108,062 nuclei from the MS/VDB, HDB/SI, PPTG/LDTG, 7N, and 12N in adult and aged mice. BF cells showed greater age-associated transcriptomic alterations than MB and BS cells, with pronounced region-specific divergence among cholinergic neurons. Intercellular communication analysis revealed BF-specific age-related changes in APP and ApoE signaling. Within this altered milieu, intrinsic transcriptional responses varied across brain regions. In aged BF cholinergic neurons, transcriptional responses were characterized by increased oxidative stress and inflammatory signatures and reduced expression of genes involved in neuronal structural maintenance. In contrast, MB and BS cholinergic neurons maintained relatively stable transcriptional profiles. These findings reveal region-specific associations between extracellular signaling and intrinsic transcriptional stress, highlighting a selective imbalance that underlies the vulnerability of BF cholinergic neurons.

Indexed as

agingbasal forebrainbrainstemcholinergic neurontranscriptome

Identifiers

PMID42890242

DOI10.1016/j.isci.2026.117778

PMCPMC13671214

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