title: Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity.
abstract: Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Eva
authors.identifier: 0000-0003-0247-0631
authors.initials: E
authors.lastname: Czirr
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Castello
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Kira I
authors.initials: KI
authors.lastname: Mosher
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.|Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Joseph M
authors.identifier: 0000-0002-8026-6292
authors.initials: JM
authors.lastname: Castellano
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.|Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.|Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Izumi V
authors.initials: IV
authors.lastname: Hinkson
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Lucin
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Bernat
authors.identifier: 0000-0003-4458-3079
authors.initials: B
authors.lastname: Baeza-Raja
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Jae Kyu
authors.identifier: 0000-0002-3992-4011
authors.initials: JK
authors.lastname: Ryu
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.|Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.|Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Lulin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.|Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Sasha N
authors.initials: SN
authors.lastname: Farina
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Belichenko
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158.|Department of Neurology, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Katerina
authors.identifier: 0000-0002-2632-1465
authors.initials: K
authors.lastname: Akassoglou
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Markus
authors.initials: M
authors.lastname: Britschgi
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO 63110.|Knight Alzheimer's Disease Research Center, Washington University Medical Center, St. Louis, MO 63110.|Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110.
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305 twc@Stanford.edu.|Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305.|Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
authors.forename: Tony
authors.identifier: 0000-0001-5893-0831
authors.initials: T
authors.lastname: Wyss-Coray
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000502:physiology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology*; D059748:Proteolysis; D013867:Thiohydantoins / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001565:Benzoates; D016177:Macrophage-1 Antigen; D013867:Thiohydantoins; C000589733:leukadherin-1