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

Autor:	Jacquet RG; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA., González Ibáñez F; 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., Picard K; 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., Funes L; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA., Khakpour M; 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., Gouras GK; Experimental Dementia Unit, BMC, Lund University, 221 84 Lund, Sweden., Tremblay MÈ; 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., Maxfield FR; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: frmaxfie@med.cornell.edu., Solé-Domènech S; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: sas2068@med.cornell.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Dec 24; Vol. 43 (12), pp. 115052. Date of Electronic Publication: 2024 Dec 06.
DOI:	10.1016/j.celrep.2024.115052
Abstrakt:	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. Competing Interests: Declaration of interests The chemical synthesis and uses of the pH-sensitive probe ApHID have been included and described in a pending patent application, for which S.S.-D. and F.R.M. are co-authors. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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