S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice
Roxane Gruel1, Baukje Bijnens2,3, Johanna Van Den Daele1
1Laboratory of Cell Biology & Histology, University of Antwerp, Wilrijk, Belgium.
Abstract:
Long considered to fluctuate between pro- and anti-inflammatory states, it has now become evident that microglia occupy a variegated phenotypic landscape with relevance to aging and neurodegeneration. However, whether specific microglial subsets converge in or contribute to both processes that eventually affect brain function is less clear. To investigate this, we analyzed microglial heterogeneity in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (Senescence-Accelerated Mouse-Prone 8, SAMP8) using cellular indexing of transcriptomes and epitopes by sequencing. We found that widespread tau pathology in K18-seeded P301L mice caused a significant change in the number and morphology of microglia, but only a mild overrepresentation of disease-associated microglia. At the cell population-level, we observed a marked upregulation of the calprotectin-encoding genes S100a8 and S100a9. In 9-month-old SAMP8 mice, we identified a unique microglial subpopulation that showed partial similarity with the disease-associated microglia phenotype and was additionally characterized by a high expression of the same calprotectin gene set. Immunostaining for S100A8 revealed that this population was enriched in the hippocampus, correlating with the cognitive impairment observed in this model. However, incomplete colocalization between their residence and markers of neuronal loss suggests regional specificity. Importantly, S100A8-positive microglia were also retrieved in brain biopsies of human AD and tauopathy patients as well as in a biopsy of an aged individual without reported pathology. Thus, the emergence of S100A8-positive microglia portrays a conspicuous commonality between accelerated aging and tauopathy progression, which may have relevance for ensuing brain dysfunction.
Insights
Microglia exhibit diverse phenotypes relevant to aging and neurodegeneration. A specific S100A8-positive microglial subset emerges in both aging and tauopathy, potentially impacting brain function.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, are increasingly recognized for their diverse phenotypes.
- These phenotypes are implicated in aging and neurodegenerative diseases like tauopathy.
- The overlap in microglial contributions to aging and neurodegeneration remains unclear.
Purpose of the Study:
- To investigate microglial heterogeneity in aging and tauopathy models.
- To identify shared microglial subsets in these conditions.
- To explore the functional relevance of these subsets in brain dysfunction.
Main Methods:
- Utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq).
- Analyzed microglial populations in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (SAMP8).
- Performed immunostaining for S100A8 and analyzed human brain biopsies.
Main Results:
- Tau pathology altered microglial number and morphology, with mild disease-associated microglia (DAM) increase.
- Both models showed upregulation of calprotectin genes (S100a8, S100a9).
- A unique S100A8-positive microglial subpopulation, similar to DAM, was found in aged mice and human samples.
Conclusions:
- S100A8-positive microglia represent a commonality between accelerated aging and tauopathy.
- This microglial subset is enriched in the hippocampus and correlates with cognitive impairment.
- The presence of S100A8-positive microglia in aged and pathological human brains suggests a role in brain dysfunction.
