A Cross-Disease Microglial Transcriptional Program Characterizes Neurodegeneration and Highlights SPP1 as a Biomarker.

Overview

1. Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy
2. PhD Program in Behavioral Neuroscience, Sapienza University of Rome, Rome, Italy
3. European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy

Abstract

Microglial cells are key players in maintaining brain homeostasis and responding to pathological conditions. Their multifaceted roles in health and disease have garnered significant attention in the context of neurodegeneration. In recent years, single‐cell transcriptomic techniques have provided unprecedented insights into microglial heterogeneity, revealing distinct subpopulations and gene expression patterns associated with neuroprotection or neurotoxicity. Here, we dissect the transcriptomic landscape of microglia by leveraging human single‐nuclei RNA sequencing datasets from multiple neurodegenerative conditions, including Amyotrophic Lateral Sclerosis, frontotemporal dementia, Alzheimer's disease, aging, and Parkinson's disease. This integrative analysis identifies distinct microglial subpopulations, reflecting functional heterogeneity across diseases and reveals a shared cross‐disease microglial transcriptional program associated with inflammatory and neurodegenerative processes. Using a machine learning framework, we further demonstrate that this transcriptional program enables robust discrimination between neurodegenerative and control samples. Experimental validation in primary microglia isolated from a mouse model of Niemann‐Pick disease type C, also known as juvenile Alzheimer's disease, supports the conservation of key components of this program and highlights Spp1 as a biomarker of disease‐associated microglia states. Overall, this study provides an improved portrait of microglia transcriptional remodeling across neurodegenerative disorders and offers a framework for identifying conserved molecular features that may inform therapeutic strategies aimed at modulating microglial activity to mitigate disease progression and foster neuroprotection.

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

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Data

Datasets cited

• geo:GSE109083, at NCBI GEO; found in the text, “RNA Sequencing Analysis”
• zenodo:7886802, at Zenodo; found in “Data Availability Statement”

Data Availability Statement

Datasets used for this work are available at Gene Expression Omnibus (GEO) repository with the following accession IDs: GSE243292 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE243292), GSE219281 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE219281), GSE174332 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE174332). Parkinson's disease dataset is available from Zenodo repository at the following link: https://doi.org/10.5281/zenodo.7886802. The bulk RNA sequencing dataset is available in GEO database under the accession ID GSE109083 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE109083).Code used for this work is available from the corresponding author upon reasonable request.

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

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Version 2, 28 September 2026

• Publisher: n/a → Wiley

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 6 keywords, 9 MeSH terms, 2 funders, 46 references.

Cite

This paper

Palma, A., Stefanelli, R., Trenta, F., Projetti, C., Massa, G., Canterini, S., & Fiorenza, M. T. (2026). A Cross-Disease Microglial Transcriptional Program Characterizes Neurodegeneration and Highlights SPP1 as a Biomarker. Glia, 74(6), e70163. https://doi.org/10.1002/glia.70163

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