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      Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes

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          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.

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          Development of monocytes, macrophages, and dendritic cells.

          Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
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            Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

            Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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              A specific amyloid-beta protein assembly in the brain impairs memory.

              Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice ( 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.
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                Author and article information

                Contributors
                (310) 423-7374 , maya.koronyo@cshs.org
                Journal
                Cell Mol Life Sci
                Cell. Mol. Life Sci
                Cellular and Molecular Life Sciences
                Springer International Publishing (Cham )
                1420-682X
                1420-9071
                14 February 2017
                14 February 2017
                2017
                : 74
                : 12
                : 2167-2201
                Affiliations
                [1 ]ISNI 0000 0001 2152 9905, GRID grid.50956.3f, Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, , Cedars-Sinai Medical Center, ; 127 S. San Vicente, AHSP A8115, Los Angeles, CA 90048 USA
                [2 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, , Perelman School of Medicine at the University of Pennsylvania, ; Philadelphia, PA 19104 USA
                [3 ]ISNI 0000 0001 2152 9905, GRID grid.50956.3f, Department of Biomedical Sciences, , Cedars-Sinai Medical Center, ; Los Angeles, CA 90048 USA
                Author information
                http://orcid.org/0000-0003-2864-8442
                Article
                2463
                10.1007/s00018-017-2463-7
                5425508
                28197669
                006a895f-379f-4d30-aec9-60a11db8d45e
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 25 August 2016
                : 7 January 2017
                : 11 January 2017
                Funding
                Funded by: BrightFocus Foundation (US)
                Award ID: A2013328S00
                Award Recipient :
                Funded by: The Cheryl and Haim Saban Foundation
                Funded by: The Marciano Family Foundation
                Categories
                Review
                Custom metadata
                © Springer International Publishing 2017

                Molecular biology
                neurodegenerative diseases,amyloid-β protein,aβ-degrading enzymes,innate immune cells,myelomonocytes,phagocytosis

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