Integrative transcriptomic analysis identifies meningeal-hippocampal immune communication in Alzheimer's disease.

Overview

1. School of Biomedical Engineering, Hainan University,No. 7, University Road, Yazhou District, Sanya, Hainan Province 572025 China

Abstract

Background: Alzheimer’s disease (AD) exhibits spatial heterogeneity, yet the mechanisms by which immune-active meninges communicate with vulnerable brain regions during disease progression remain unclear. This study aimed to investigate meninges-hippocampus crosstalk and map the communication patterns during AD pathology development.

Methods: We employed 5xFAD transgenic and PS19 tau-pathology mouse models and integrated bulk RNA sequencing, proteomics, and spatial transcriptomics across time-course analyses to distinguish AD pathology from normal aging processes. Transcription factor activity inference was coupled with ligand-receptor dynamics analysis to examine regulatory modules in homeostatic and disease-associated microglia.

Results: We identified structure-specific disease genes, including a robust 19-gene hippocampal signature that was reproducible across an independent 5xFAD dataset and PS19 tau-pathology dataset. Spatial analysis defined a disease progression axis that transferred to the independent spatial dataset, where meningeal spots were enriched in advanced disease progression layers and disease modules showed consistent gradients. Ligand-receptor and microglial-state LRaxis analyses further supported candidate communication axes associated with pathology gradients and state-specific regulatory modules in both homeostatic and disease-associated microglia.

Conclusions: Our spatial framework supports the meninges as a candidate modulatory interface associated with hippocampal pathology in AD mouse models. These mouse-derived, computationally inferred ligand-receptor and regulatory modules should be considered hypothesis-generating candidates that require validation in human AD tissues and functional perturbation studies before translational relevance can be inferred.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08414-5.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:33582613, at figshare; found in DataCite

Other data links

• ebi.ac.uk/biostudies/arrayexpress, EMBL-EBI; found in “Data availability”
• ncbi.nlm.nih.gov/geo, NCBI; found in “Data availability”

Data availability

All datasets used in this study are publicly available. E-MTAB-16006 from ArrayExpress (https://www.ebi.ac.uk/biostudies/arrayexpress), GSE198226, GSE218728, GSE218360 and GSE174321 from Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/), and PXD030348 from ProteomeXchange (https://www.proteomexchange.org/). Relevant codes used for data analysis are available from https://github.com/yccbio/AD/blob/main/multiomics_code.

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, 7 authors, 4 keywords, 11 MeSH terms, 1 funder, 34 references.

Cite

This paper

Yan, C., Chen, Z., Yan, Y., Wang, M., Chen, W., Zhou, F., & Liu, Q. (2026). Integrative transcriptomic analysis identifies meningeal-hippocampal immune communication in Alzheimer's disease. Journal of translational medicine, 24(1), 1172. https://doi.org/10.1186/s12967-026-08414-5

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