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The dark microglial subset displays ultrastructural and metabolic alterations in an aged mouse model of beta-amyloid pathology

Principal Investigator:
  • Marie-Kim St-Pierre, Université Laval
  • Seger-van Tol Family

Project Overview

Dr. Hubert van Tol Travel Fellowship

AIMS: Recent technical advances helped to reveal the considerable heterogeneity of microglia, the resident immune cells of the central nervous system. One of these microglial subsets, the dark microglia (DM), was characterized by ultrastructural signs of cellular stress such as dilated endoplasmic reticulum (ER), altered mitochondria and loss of heterochromatin pattern. These dark cells were previously identified notably near amyloid beta plaques in age-matched APP-PS1 mice, a mouse model of amyloid beta deposition. However, their ultrastructural features and interactions with hallmarks of amyloid deposition (plaques, dystrophic neurites) were not yet investigated in aging.

METHODS: Using high-magnification chip mapping by scanning electron microscopy, we first analyzed the density of both typical and DM in the ventral hippocampus CA1 (strata lacunosum-moleculare and radiatum) of 20-month-old male WT versus APP-PS1 mice.

RESULTS: In the stratum lacunosum-moleculare, dark microglia represented nearly 43% of all microglial cells found near AD hallmarks. We found DM interacting more with dystrophic neurites, while contacting less healthy synaptic elements, myelinated axons and brain vasculature compared to typical microglia.

CONCLUSIONS: The present study further highlights the close interactions between DM and amyloid beta deposition hallmarks, suggesting a specialized involvement, whether beneficial or detrimental, compared to typical microglia in this context. Further investigations into the prevalence and parenchymal interactions of DM with Alzheimer’s disease hallmarks will be performed in postmortem brain samples from Alzheimer’s patients and aged-matched controls. Studying DM close interactions with disease hallmarks could help us find new therapeutic targets modulating these cells in a context-dependent manner.