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. We believe that pharmacological enhancement of lysosomal synapse pH using promoters of lysosomal biogenesis would dramatically increase degradation of fibrillar Aβ by microglia. Additionally, we will also discuss a novel, unpublished methodology to measure macrophage lysosomal pH in mouse brain by intravital ratiometric pH imaging. Dextran polymers labeled with our pH-sensitive probe ApHID (pKa ~5) and a  second, pH-independent dye, injected subcutaneously in mice are taken up by brain macrophages and reach their lysosomal compartments, where they serve as pH-sensors. We are currently adapting this methodology to label lysosomal synapses and demonstrate microglial digestive exophagy of Aβ deposits in vivo in AD model mice.

More information:

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