Repopulated microglia induce expression of Cxcl13 with differential changes in Tau phosphorylation but do not impact amyloid pathology

• Published in: Journal of neuroinflammation Vol. 19; no. 1; pp. 1 - 173
• Main Authors: Karaahmet, Berke, Le, Linh, Mendes, Monique S, Majewska, Ania K, O'Banion, M. Kerry
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 04-07-2022; BioMed Central; BMC
• Subjects: Aging; Alzheimer's disease; Animal cognition; Animal models; Behavior; Brain research; Chemokines; Colony-stimulating factor 1; CXCL13 protein; Development and progression; Diet; Epitopes; Flow cytometry; Gene expression; Genetic aspects; Health aspects; Hippocampus; Homeostasis; Immunohistochemistry; Inflammation; Microglia; Neurodegenerative diseases; Neurological research; Pathogenesis; Pathology; Phosphorylation; PLX5622; Presenilin 1; RNAseq; Tau protein; Tau proteins; United States
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-022-02532-9

Abstract
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 CD45
int/+
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.