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Updated: Nov 16, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Distinct amyloid-β and tau-associated microglia profiles in Alzheimer's disease
Emma Gerrits1, Nieske Brouwer1, Susanne M Kooistra1
1Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen and University Medical Center Groningen (UMCG), Antonius Deusinglaan 1, 9713AV, Groningen, the Netherlands.
Abstract:
Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-β and intraneuronal hyperphosphorylated tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-β and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-β plaques or both amyloid-β plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-β load and localized to amyloid-β plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with overt tau pathology. This full characterization of human disease-associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
Insights
Researchers identified two distinct human microglia phenotypes associated with Alzheimer's disease (AD) pathology. Microglia states correlated with amyloid-β and tau loads, offering new therapeutic targets for AD.
Area of Science:
- Neuroscience
- Immunology
- Genomics
Background:
- Alzheimer's disease (AD) is the leading cause of dementia, characterized by amyloid-β plaques and tau tangles.
- Microglia, the brain's immune cells, play a crucial role in CNS homeostasis and are implicated in AD pathogenesis.
- Previous studies in mouse models suggested a phagocytic microglia phenotype in AD, but human microglia responses remained unclear.
Purpose of the Study:
- To investigate the transcriptional profiles of human microglia in response to Alzheimer's disease (AD) pathology.
- To identify distinct human microglia phenotypes associated with amyloid-β and tau pathology.
- To explore potential therapeutic targets for AD by characterizing disease-associated microglia.
Main Methods:
- Single-nucleus RNA sequencing (snRNAseq) was performed on 482,472 nuclei from human brain samples.
- Samples included non-demented controls, AD brains with amyloid-β plaques, and AD brains with both amyloid-β and tau pathology.
- Microglia transcriptional profiles were analyzed to identify distinct cell populations and their association with AD pathologies.
Main Results:
- Two distinct AD pathology-associated microglia expression profiles were identified within the microglia population.
- AD1-microglia abundance correlated with amyloid-β load and localized to plaques.
- AD2-microglia abundance correlated with phospho-tau load and were more prevalent in samples with tau pathology.
Conclusions:
- This study fully characterizes human disease-associated microglia phenotypes.
- Findings provide novel insights into the pathophysiological role of microglia in Alzheimer's disease.
- Identified microglia phenotypes offer potential targets for microglia-state-specific therapeutic strategies in AD.
