title: Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease.
abstract: Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer's disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Lucin
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: O'Brien
authors.forename: Gregor
authors.initials: G
authors.lastname: Bieri
authors.forename: Eva
authors.initials: E
authors.lastname: Czirr
authors.forename: Kira I
authors.initials: KI
authors.lastname: Mosher
authors.forename: Rachelle J
authors.initials: RJ
authors.lastname: Abbey
authors.forename: Diego F
authors.initials: DF
authors.lastname: Mastroeni
authors.forename: Joseph
authors.initials: J
authors.lastname: Rogers
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism* / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000378:metabolism* / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology*; D011971:Receptors, Immunologic / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism* / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D018955:CD36 Antigens; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D033921:Vesicular Transport Proteins