Astrocytes display ultrastructural alterations and heterogeneity in the hippocampus of aged APP‑PS1 mice and human post‑mortem brain samples




St-Pierre, Marie-Kim
Carrier, Micaël
González Ibáñez, Fernando
Khakpour, Mohammadparsa
Wallman, Marie‑Josée
Parent, Martin
Tremblay, Marie-Ève

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Journal of Neuroinflammation


The past decade has witnessed increasing evidence for a crucial role played by glial cells, notably astrocytes, in Alzheimer’s disease (AD). To provide novel insights into the roles of astrocytes in the pathophysiology of AD, we performed a quantitative ultrastructural characterization of their intracellular contents and parenchymal interactions in an aged mouse model of AD pathology, as aging is considered the main risk factor for developing AD. We compared 20-month-old APP-PS1 and age-matched C57BL/6J male mice, among the ventral hippocampus CA1 strata lacunosum-moleculare and radiatum, two hippocampal layers severely affected by AD pathology. Astrocytes in both layers interacted more with synaptic elements and displayed more ultrastructural markers of increased phagolysosomal activity in APP-PS1 versus C57BL6/J mice. In addition, we investigated the ultrastructural heterogeneity of astrocytes, describing in the two examined layers a dark astrocytic state that we characterized in terms of distribution, interactions with AD hallmarks, and intracellular contents. This electron-dense astrocytic state, termed dark astrocytes, was observed throughout the hippocampal parenchyma, closely associated with the vasculature, and possessed several ultrastructural markers of cellular stress. A case study exploring the hippocampal head of an aged human postmortem brain sample also revealed the presence of a similar electron-dense, dark astrocytic state. Overall, our study provides the first ultrastructural quantitative analysis of astrocytes among the hippocampus in aged AD pathology, as well as a thorough characterization of a dark astrocytic state conserved from mouse to human.


We would like to thank Dr. Nathalie Vernoux and Mr. Hassan El Hajj for the perfusion of the mice. We are also thankful to Dr. Luc Vallières for generously providing the APP-PS1 mice used in the study. We acknowledge with respect the Lekwungen peoples on whose traditional territory the University of Victoria stands, and the Songhees, Esquimalt and WSÁNEĆ peoples whose historical relationships with the land continue to this day.


Astrocytes, Heterogeneity, Dark astrocytes, Ultrastructure, Aging, Alzheimer’s disease, APP-PS1 mice, Human post-mortem brain samples


St-Pierre, M-K., Carrier, M., González Ibáñez, F., Khakpour, M., Wallman, M-J., Parent, M., & Tremblay, M-È. (2023). Astrocytes display ultrastructural alterations and heterogeneity in the hippocampus of aged APP‑PS1 mice and human post‑mortem brain samples. Journal of Neuroinflammation, 20(73).