Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology

Journal of Neuroinflammation

Serge Rivest¹  Julie C. Savage¹  Marie-Ève Tremblay¹  Hassan El Hajj¹  Kanchan Bisht¹  Luc Vallières¹  Martin Parent² 

[1] Axe neurosciences, Centre de recherche du CHU de Québec-Université Laval;Département de psychiatrie et de neurosciences, Faculté de médecine, Université Laval;

关键词: Microglia;    Alzheimer’s disease;    Mouse model;    Ultrastructure;    Electron microscopy;   

DOI  :  10.1186/s12974-019-1473-9

来源: DOAJ

【 摘 要 】

Abstract Background Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid β (fΑβ) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, Aβ drives a robust and prolonged inflammatory response via its recognition by microglia, the brain’s immune cells. Microglial reactivity to fAβ plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cognitive decline in AD. Methods In the current study, we performed correlative light, transmission, and scanning electron microscopy to provide insights into microglial structural and functional heterogeneity. We analyzed microglial cell bodies and processes in areas containing fAβ plaques and neuronal dystrophy, dystrophy only, or appearing healthy, among the hippocampus CA1 of 14-month-old APPSwe-PS1Δe9 mice versus wild-type littermates. Results Our quantitative analysis revealed that microglial cell bodies in the AD model mice were larger and displayed ultrastructural signs of cellular stress, especially nearby plaques. Microglial cell bodies and processes were overall less phagocytic in AD model mice. However, they contained increased fibrillar materials and non-empty inclusions proximal to plaques. Microglial cell bodies and processes in AD model mice also displayed reduced association with extracellular space pockets that contained debris. In addition, microglial processes in healthy subregions of AD model mice encircled synaptic elements more often compared with plaque-associated processes. These observations in mice were qualitatively replicated in post-mortem hippocampal samples from two patients with AD (Braak stage 5). Conclusion Together, our findings identify at the ultrastructural level distinct microglial transformations common to mouse and human in association with amyloid pathology.

【 授权许可】

Unknown