Dysfunctional microglial phenotype in the hippocampus of aged amyloidogenic Alzheimer's model: Developing topics. (7th December 2020)

• Record Type: Journal Article
• Authors: Nuñez‐Diaz, Cristina; Sanchez‐Mejias, Elisabeth; Arboledas, Angela Gomez; Mejias‐Ortega, Marina; Sanchez‐Varo, Raquel; Davila, Jose Carlos; Vitorica, Javier; Gutierrez, Antonia
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.047411
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The accumulation of amyloid beta (Aβ), giving rise to soluble toxic oligomers and insoluble amyloid plaques, is one of the main hallmarks of Alzheimer's disease (AD). Aβ pathology triggers an inflammatory response mediated by activated astroglia and microglia. However, the specific role of the latter in the progression of AD and their relationship with plaques are not fully understood yet. Here we have analyzed, at cellular and subcellular levels, the progression of amyloid pathology and the associated activated microglia in the hippocampus of the model APP750SL /PS1M146L . Method: Immunohistochemistry for light and electron microscopy were performed in hippocampal samples from 4‐ to 18‐month‐old APP750SL /PS1M146L mice. Quantifications were done by image analysis and stereology. Result: There is an age‐dependent increase in the amyloid burden and plaques grow, increasing both the size of the core and the halo, in the hippocampus of APP/PS1 model. Besides, a correlation exists between the size of plaques and the number of neuritic dystrophies surrounding them. Amyloid plaques are surrounded by activated microglia, showing a transcriptomic DAM profile. Microglial processes intertwine with the amyloid fibrils, acting as a barrier that isolates plaques and phagocytose Aβ, which might be toxic for these cells. Therefore, microglia surrounding amyloid plaques show ultrastructural signs of dysfunction, which might lead to a worsening of amyloid pathology and neurodegeneration. Conclusion: Microglia surrounding amyloid plaques suffer a degenerative process with the progression of the pathology, which might affect their functions of phagocytosis/isolation/compaction of amyloid plaques. This could contribute to the progression of AD, with the plaques releasing highly toxic soluble Aβ oligomers to the brain parenchyma. Therefore, restoring microglial function or renewing this population might be a promising therapeutic approach for AD. Supported by: Instituto de Salud Carlos III, co‐financed by FEDER funds from European Union, projects PI18/01557 (to AG) and PI18/01556 (to JV), by CIBERNED (to AG and JV), and by Junta de Andalucia project UMA18‐FEDERJA211 (to AG).