Microglia degrade Alzheimer’s amyloid-beta deposits extracellularly via digestive exophagy

How microglia digest Alzheimer’s fibrillar amyloid-beta (Aβ) plaques that are too large to be phagocytosed is not well understood. Here, we show that primary microglial cells create acidic extracellular compartments, lysosomal synapses, on model plaques and digest them with exocytosed lysosomal enzymes. This mechanism, called digestive exophagy, is confirmed by electron microscopy in 5xFAD mouse brains, which shows that a lysosomal enzyme, acid phosphatase, is secreted toward the plaques in structures resembling lysosomal synapses. Signaling studies demonstrate that the PI3K-AKT pathway modulates the formation of lysosomal synapses, as inhibition of PI3K1β or AKT1/2 reduces both lysosome exocytosis and actin polymerization, both required for the formation of the compartments. Finally, we show that small fibrils of Aβ previously internalized and trafficked to lysosomes are exocytosed toward large Aβ aggregates by microglia. Thus, the release of lysosomal contents during digestive exophagy may also contribute to the spread and growth of fibrillar Aβ. [Display omitted] •Microglia use digestive exophagy to digest Aβ plaques that cannot be phagocytosed•Microglia form extracellular acidic compartments -lysosomal synapses- on Aβ plaques•Lysosomal synapses are acidic and receive lysosomal enzymes via lysosomal exocytosis•Microglia also secrete indigestible intralysosomal Aβ fibrils into lysosomal synapses Jacquet et al. shows that microglia use digestive exophagy to engage large Aβ deposits that cannot be phagocytosed, forming acidic extracellular compartments on the aggregates into which lysosomal enzymes are exocytosed. The PI3K-AKT pathway modulates this process. Microglia also exocytose intralysosomal undigested fibrillar Aβ toward extracellular aggregates, potentially contributing to plaque growth.