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AD/PD 2023 | How do microglia digest large amyloid beta aggregates?

Santiago Solé-Domènech, PhD, and Rudy Gregory Jacquet, PhD Candidate, Weill Cornell Medicine, New York, NY, discuss their research into the mechanisms by which microglia engage in the clearance of large amyloid beta (Aβ) aggregates. Previous research has shown that macrophages form lysosomal synapses – extracelluar, surface connected compartments – for the degradation of large aggregates. Using radiometric pH imaging, super-resolution Airyscan microscopy, and 3D reconstruction, the team demonstrated that this process of digestive exophagy also occurs in microglia in the presence of synthetic Aβ deposits. Imaging revealed the formation of extracellular, partially sealed compartments into which lysosomal contents was secreted to promote degradation. Rapid actin polymerization was noted at the connection between the cell and the extracellular compartment. Having confirmed the process of digestive exophagy in microglia, Dr Solé-Domènech and Mr Jacquet wanted to assess its role in the interaction between microglia and Aβ deposits. Using a system of surface-bound plaque incubated with microglia, plaque degradation was seen to dramatically taper off after 24 hours, before picking back up slightly after 3 days. Dr Solé-Domènech explains that they believe this demonstrates the occurrence of extracellular degradation after microglia become loaded with fibrils and can no longer take up Aβ. This interview took place at the AD/PD™ 2023 congress in Gothenburg, Sweden.

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