Recently, we described a mechanism used by microglia to partially digest Alzheimer’s disease (AD) fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed. To digest the aggregates, microglia create tightly sealed regions –lysosomal synapses- on the target, into which lysosomal contents and protons are secreted by lysosomal exocytosis. This process has been called digestive exophagy (Jacquet et al, Cell Reports 2024) and it is very similar to the well-known degradative mechanisms used by osteoclasts during bone resorption. When we measured the pH of lysosomal synapses in cell culture, we found that the compartments were only mildly acidic (pH ~6.5). Previously, we found that microglia are only able to digest fibrillar Aβ efficiently when full lysosomal acidification is achieved (pH 4.5-5.0, Majumdar et al. MBC 2012; Sole-Domenech et al. PNAS 2018). Our hypothesis is that, due to incomplete acidification, enzymes exocytosed into lysosomal synapses are not able to degrade fibrillar Aβ plaques efficiently. Additionally, we will also discuss a novel, unpublished methodology to measure macrophage and microglia lysosomal pH in the intact mouse brain by intravital ratiometric pH imaging. Dextran polymers labeled with our pH-sensitive probe ApHID (Sole-Domenech et al., Cell Rep Methods, 2025) and a  second, pH-independent dye, are injected into mice and taken up by brain phagocytes. The polymers reach lysosomal compartments, where they serve as pH sensors. In preliminary measurements, meningeal phagocytes and microglia did not fully acidify their lysosomes (pH 5.4.5.6), which might be due to a role played by these cells in antigen presentation. We believe that pharmacological enhancement of lysosomes and lysosomal synapse acidification using promoters of lysosomal biogenesis might dramatically increase the capacity of brain phagocytes to degrade pathogenic fibrils, including fibrillar Aβ.

More information: https://vivo.weill.cornell.edu/display/cwid-sas2068