Stereo-seq of the prefrontal cortex in aging and Alzheimer’s disease

Yun Gong, Mohammad Haeri, Xiao Zhang, Yisu Li, Anqi Liu, Di Wu, Qilei Zhang, S. Michal Jazwinski, Xiang Zhou, Xiaoying Wang, Kai Zhang, Lindong Jiang, Yi-Ping Chen, Xiaoxin Yan, Russell H. Swerdlow (), Hui Shen () and Hong-Wen Deng ()
Additional contact information
Yun Gong: Tulane University
Mohammad Haeri: University of Kansas Medical Center
Xiao Zhang: Tulane University
Yisu Li: Tulane University
Anqi Liu: Tulane University
Di Wu: Tulane University
Qilei Zhang: Central South University
S. Michal Jazwinski: Tulane University School of Medicne
Xiang Zhou: University of Michigan
Xiaoying Wang: Tulane University School of Medicine
Kai Zhang: University at Albany
Lindong Jiang: Tulane University
Yi-Ping Chen: Tulane University
Xiaoxin Yan: Central South University
Russell H. Swerdlow: University of Kansas Medical Center
Hui Shen: Tulane University
Hong-Wen Deng: Tulane University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Aging increases the risk for Alzheimer’s disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions in laminar structure, and exposed AD-related shifts in layer-to-layer and cell-cell interactions. Notably, we identified genes highly upregulated in stressed neurons and nearby glial cells, where AD diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis highlighted three neuronal modules linked to neuroprotection, protein dephosphorylation, and Aβ regulation, with all modules downregulated as AD progresses. We identified ZNF460 as a transcription factor regulating these modules, offering a potential therapeutic target. In summary, this spatial transcriptome atlas provides valuable insight into AD’s molecular mechanisms.

Date: 2025
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DOI: 10.1038/s41467-024-54715-y

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