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Updated: Dec 31, 2025
Author Spotlight: Exploring Sex-Specific Glial Signatures and Therapeutic Leads for Alzheimer's Disease
Published on: May 20, 2024
Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in
Yingyue Zhou1, Wilbur M Song1, Prabhakar S Andhey1
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
Insights
Alzheimer's disease (AD) involves glial cells. While TREM2 (triggering receptor expressed on myeloid cells 2) drives microglia changes in mice, human AD shows distinct glial responses, yet TREM2 remains crucial for microglia reactivity in both species.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Glia, including microglia and oligodendrocytes, play roles in Alzheimer's disease (AD) pathogenesis.
- Genetic variants in TREM2 (triggering receptor expressed on myeloid cells 2) are linked to increased AD risk.
- TREM2 signaling is known to regulate disease-associated microglia (DAM) in AD mouse models.
Purpose of the Study:
- To investigate gene-expression changes in glia during AD pathology and in relation to TREM2 function.
- To compare glial responses in mouse models of AD with human AD.
- To determine the role of TREM2 in species-specific glial phenotypes in AD.
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) was employed to analyze gene-expression profiles.
- Studies were conducted in 5XFAD mouse models of AD and in human AD brain samples.
- Analysis focused on identifying distinct glial cell populations and their molecular signatures.
Main Results:
- Confirmed TREM2-dependent DAM in mice and identified a novel reactive oligodendrocyte population (Serpina3n+, C4b+).
- Human AD microglia exhibited an IRF8-driven reactive signature, distinct from mouse models.
- Human oligodendrocytes showed impaired myelination and metabolic adaptation, while astrocytes displayed weakened neuronal metabolic coordination.
- Microglial reactivity was reduced in human carriers of TREM2 variants (R47H, R62H) compared to non-carriers.
Conclusions:
- Significant species-specific differences exist in glial responses during AD, despite conserved roles for TREM2.
- TREM2 is essential for microglial activation in both mouse models and human AD.
- Oligodendrocyte and astrocyte dysfunction contribute to AD pathogenesis, highlighting complex glial interactions.
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