title: Clearance of cerebral Aβ in Alzheimer's disease: reassessing the role of microglia and monocytes.
abstract: Deficiency in cerebral amyloid β-protein (Aβ) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of misfolded Aβ in the brain is believed to be a net result of imbalance between its production and removal. This in turn may trigger neuroinflammation, progressive synaptic loss, and ultimately cognitive decline. Clearance of cerebral Aβ is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Recent studies have highlighted a new, unexpected role for peripheral monocytes and macrophages in restricting cerebral Aβ fibrils, and possibly soluble oligomers. In AD transgenic (ADtg) mice, monocyte ablation or inhibition of their migration into the brain exacerbated Aβ pathology, while blood enrichment with monocytes and their increased recruitment to plaque lesion sites greatly diminished Aβ burden. Profound neuroprotective effects in ADtg mice were further achieved through increased cerebral recruitment of myelomonocytes overexpressing Aβ-degrading enzymes. This review summarizes the literature on cellular and molecular mechanisms of cerebral Aβ clearance with an emphasis on the role of peripheral monocytes and macrophages in Aβ removal.
authors.affiliation: Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 127 S. San Vicente, AHSP A8115, Los Angeles, CA, 90048, USA.|Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Zuroff
authors.affiliation: Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 127 S. San Vicente, AHSP A8115, Los Angeles, CA, 90048, USA.
authors.forename: David
authors.initials: D
authors.lastname: Daley
authors.affiliation: Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 127 S. San Vicente, AHSP A8115, Los Angeles, CA, 90048, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.affiliation: Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 127 S. San Vicente, AHSP A8115, Los Angeles, CA, 90048, USA. maya.koronyo@cshs.org.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. maya.koronyo@cshs.org.
authors.forename: Maya
authors.identifier: 0000-0003-2864-8442
authors.initials: M
authors.lastname: Koronyo-Hamaoui
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D016229:Amyloid beta-Peptides
keywords: Amyloid-β protein; Aβ-degrading enzymes; Innate immune cells; Myelomonocytes; Neurodegenerative diseases; Phagocytosis