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Updated: Sep 5, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Repopulated microglia induce expression of Cxcl13 with differential changes in Tau phosphorylation but do not impact
Berke Karaahmet1, Linh Le1, Monique S Mendes1,2
1Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA.
Background:
Adult microglia rely on self-renewal through division to repopulate and sustain their numbers. However, with aging, microglia display morphological and transcriptional changes that reflect a heightened state of neuroinflammation. This state threatens aging neurons and other cells and can influence the progression of Alzheimer's disease (AD). In this study, we sought to determine whether renewing microglia through a forced partial depletion/repopulation method could attenuate AD pathology in the 3xTg and APP/PS1 mouse models.
Methods:
We pharmacologically depleted the microglia of two cohorts of 21- to 22-month-old 3xTg mice and one cohort of 14-month-old APP/PS1 mice using PLX5622 formulated in chow for 2 weeks. Following depletion, we returned the mice to standard chow diet for 1 month to allow microglial repopulation. We assessed the effect of depletion and repopulation on AD pathology, microglial gene expression, and surface levels of homeostatic markers on microglia using immunohistochemistry, single-cell RNAseq and flow cytometry.
Results:
Although we did not identify a significant impact of microglial repopulation on amyloid pathology in either of the AD models, we observed differential changes in phosphorylated-Tau epitopes after repopulation in the 3xTg mice. We provide evidence that repopulated microglia in the hippocampal formation exhibited changes in the levels of homeostatic microglial markers. Lastly, we identified novel subpopulations of microglia by performing single-cell RNAseq analysis on CD45int/+ cells from hippocampi of control and repopulated 3xTg mice. In particular, one subpopulation induced after repopulation is characterized by heightened expression of Cxcl13.
Conclusion:
Overall, we found that depleting and repopulating microglia causes overexpression of microglial Cxcl13 with disparate effects on Tau and amyloid pathologies.
Insights
Renewing aged microglia by depletion and repopulation altered tau pathology but not amyloid pathology in Alzheimer's disease models. This process led to increased Cxcl13 expression in repopulated microglia.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Adult microglia are crucial for brain homeostasis and rely on self-renewal.
- Aging impairs microglia, leading to neuroinflammation and exacerbating Alzheimer's disease (AD) pathology.
- Microglial dysfunction is a key factor in neurodegenerative diseases.
Purpose of the Study:
- To investigate if forced microglial renewal via depletion and repopulation can mitigate AD pathology.
- To assess the impact of microglial repopulation on amyloid and tau pathologies in AD mouse models.
- To characterize transcriptional and surface marker changes in repopulated microglia.
Main Methods:
- Pharmacological depletion of microglia using PLX5622 in aged 3xTg and APP/PS1 mice.
- A one-month repopulation period following depletion.
- Assessment of AD pathology, microglial gene expression (single-cell RNAseq), and surface markers (flow cytometry, immunohistochemistry).
Main Results:
- Microglial repopulation did not significantly alter amyloid pathology in either AD model.
- Differential changes in phosphorylated-tau epitopes were observed in 3xTg mice post-repopulation.
- Repopulated microglia showed altered homeostatic marker levels and novel subpopulations, including Cxcl13-expressing cells.
Conclusions:
- Microglial depletion and repopulation induce Cxcl13 overexpression.
- This intervention has disparate effects on tau and amyloid pathologies in AD models.
- Microglial renewal strategies may offer therapeutic avenues for neuroinflammation in AD.
