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Updated: Jul 28, 2025
Author Spotlight: Exploring Sex-Specific Glial Signatures and Therapeutic Leads for Alzheimer's Disease
Published on: May 20, 2024
Human microglia show unique transcriptional changes in Alzheimer's disease
Katherine E Prater1, Kevin J Green1, Sainath Mamde1
1Department of Neurology, University of Washington, Seattle, WA, USA.
Abstract:
Microglia, the innate immune cells of the brain, influence Alzheimer's disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, the regulation of which is not fully understood, complicating therapeutics development. To better define the transcriptomic phenotypes and gene regulatory networks associated with AD, we enriched for microglia nuclei from 12 AD and 10 control human dorsolateral prefrontal cortices (7 males and 15 females, all aged >60 years) before single-nucleus RNA sequencing. Here we describe both established and previously unrecognized microglial molecular phenotypes, the inferred gene networks driving observed transcriptomic change, and apply trajectory analysis to reveal the putative relationships between microglial phenotypes. We identify microglial phenotypes more prevalent in AD cases compared with controls. Further, we describe the heterogeneity in microglia subclusters expressing homeostatic markers. Our study demonstrates that deep profiling of microglia in human AD brain can provide insight into microglial transcriptional changes associated with AD.
Insights
Researchers identified distinct microglial phenotypes in Alzheimer's disease (AD) brains using single-nucleus RNA sequencing. This deep profiling reveals new insights into brain immune cell changes and potential therapeutic targets for AD.
Area of Science:
- Neuroscience
- Immunology
- Genomics
Background:
- Microglia are key brain immune cells influencing Alzheimer's disease (AD) progression.
- Understanding microglial diversity and regulation is crucial for developing effective AD therapeutics.
- Current knowledge of microglial transcriptomic phenotypes in human AD brains is limited.
Purpose of the Study:
- To define transcriptomic phenotypes and gene regulatory networks of microglia in human AD brains.
- To identify microglial subpopulations and their relationship to AD pathology.
- To uncover novel molecular targets for AD therapy.
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) of microglia nuclei from human dorsolateral prefrontal cortices (12 AD, 10 control).
- Bioinformatic analysis to identify microglial phenotypes, gene networks, and subclusters.
- Trajectory analysis to infer relationships between identified microglial phenotypes.
Main Results:
- Characterization of established and novel microglial molecular phenotypes in AD brains.
- Identification of specific microglial phenotypes more prevalent in AD cases compared to controls.
- Description of heterogeneity within microglial subclusters, including those expressing homeostatic markers.
Conclusions:
- Deep transcriptomic profiling of human AD brain microglia provides critical insights into AD-associated cellular changes.
- Identified microglial phenotypes and networks offer potential targets for future Alzheimer's disease therapeutics.
- The study highlights significant heterogeneity and AD-specific alterations in brain microglia.
