Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer's disease pathology and in human post-mortem brain samples

Date

2022

Authors

St-Pierre, Marie-Kim
Carrier, Micaël
González Ibáñez, Fernando
Šimončičová, Eva
Wallman, Marie‑Josée
Vallières, Luc
Parent, Martin
Tremblay, Marie-Ève

Journal Title

Journal ISSN

Volume Title

Publisher

Journal of Neuroinflammation

Abstract

A diverse heterogeneity of microglial cells was previously described in Alzheimer’s disease (AD) pathology, including dark microglia, a state characterized by ultrastructural markers of cellular stress. To provide novel insights into the roles of dark microglia during aging in the context of AD pathology, we performed a quantitative density and ultrastructural analysis of these cells using high-throughput scanning electron microscopy in the ventral hippocampus CA1 stratum lacunosum-moleculare of 20-month-old APP-PS1 vs C57BL/6J male mice. The density of dark microglia was significantly higher in APP-PS1 vs C57BL/6J mice, with these cells accounting for nearly half of all microglia observed near amyloid-beta (Aβ) plaques. This dark microglial state interacted more with dystrophic neurites compared to other APP-PS1 microglia and possessed glycogen granules, associated with a metabolic shift toward glycolysis, which provides the first ultrastructural evidence of their presence in microglia. Dark microglia were further observed in aging human post-mortem brain samples showing similar ultrastructural features as in mouse. Overall, our results provide a quantitative ultrastructural characterization of a microglial state associated with cellular stress (i.e., dark microglia) that is primarily restricted near Aβ plaques and dystrophic neurites. The presence of this microglial state in the aging human post-mortem brain is further revealed.

Description

We would like to thank Dr. Nathalie Vernoux and Hassan El Hajj for their help with the perfusion of the mice.

Keywords

Alzheimer's disease, microglia, dark microglia, ultrastructure, human post-mortem brain samples, dystrophic neurites, amyloid-beta

Citation

St-Pierre, M-K., Carrier, M., González Ibáñez, F., Wallman, M-J., Vallières, L., Parent, M., & Tremblay, M-È. (2022). Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer's disease pathology and in human post-mortem brain samples. Journal of Neuroinflammation, 19(235). https://doi.org/10.1186/s12974-022-02595-8