Microglia degrade Alzheimer’s amyloid-beta deposits extracellularly via digestive exophagy
Rudy G. Jacquet,
Fernando González Ibáñez,
Katherine Picard,
Lucy Funes,
Mohammadparsa Khakpour,
Gunnar K. Gouras,
Marie-Ève Tremblay,
Frederick R. Maxfield,
Santiago Solé-Domènech
Affiliations
Rudy G. Jacquet
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA
Fernando González Ibáñez
Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC G1E 6W2, Canada; Département de Médecine Moléculaire, Université Laval, Québec City, QC G1V 0A6, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
Katherine Picard
Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC G1E 6W2, Canada; Département de Médecine Moléculaire, Université Laval, Québec City, QC G1V 0A6, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
Lucy Funes
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA
Mohammadparsa Khakpour
Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC G1E 6W2, Canada; Département de Médecine Moléculaire, Université Laval, Québec City, QC G1V 0A6, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada
Gunnar K. Gouras
Experimental Dementia Unit, BMC, Lund University, 221 84 Lund, Sweden
Marie-Ève Tremblay
Axe Neurosciences, Centre de Recherche du CHU de Québec-Université Laval, Québec, QC G1E 6W2, Canada; Département de Médecine Moléculaire, Université Laval, Québec City, QC G1V 0A6, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC V8W 2Y2, Canada; Neurology and Neurosurgery Department, McGill University, Montréal, QC H3A 2B4, Canada; Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Centre for Advanced Materials and Related Technology (CAMTEC) and Institute on Aging and Lifelong Health (IALH), University of Victoria, Victoria, BC V8W 2Y2, Canada
Frederick R. Maxfield
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA; Corresponding author
Santiago Solé-Domènech
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA; Corresponding author
Summary: 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.
