• Neuroscience · Sep 2020

    Microglia Do Not Take Up Soluble Amyloid-beta Peptides, But Partially Degrade Them by Secreting Insulin-degrading Enzyme.

    • Hongjun Fu, Bin Liu, Liangping Li, and Cynthia A Lemere.
    • Department of Neuroscience, Chronic Brain Injury, Discovery Themes, The Ohio State University, Columbus, OH, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: Hongjun.Fu@osumc.edu.
    • Neuroscience. 2020 Sep 1; 443: 30-43.

    AbstractMicroglia play important roles in the pathogenesis of Alzheimer's disease (AD), in part, by affecting the clearance of amyloid-β (Aβ) peptides. Most studies, however, used synthetic soluble Aβ (sAβ) at higher concentrations. The exact mechanisms underlying microglia-mediated clearance of physiological sAβ at very low concentrations remain unclear. Here we reported that there were much more Iba-1- and CD68-positive microglia and significantly less sAβ left in the brain of adult mice 5 days after the surgery of sAβ microinjection compared to 2 h after the surgery (p < 0.05). However, very few Iba-1- and CD68-positive microglia co-localized with microinjected fluorescently labeled sAβ (FLsAβ42) 5 days after the surgery. Also, there was no co-localization of FLsAβ42 with a lysosomal marker (LAMP-1) 5 days after the surgery. There was no significant difference in the percentage of Aβ+/PE-CD11b+/APC-CD45low microglia between the control group and the group microinjected with TBS-soluble Aβ extracted from the brains of AD patients (p > 0.05). The degradation of physiological sAβ was prevented by a highly selective insulin-degrading enzyme inhibitor (Ii1) but not by a phagocytosis inhibitor (polyinosinic acid) or pinocytosis inhibitor (cytochalasin B) in vitro. Furthermore, the reduction of synthetic and physiological sAβ in the brain was partially prevented by the co-injection of Ii1 in vivo (p < 0.05). Our results demonstrate that microglia do not take up synthetic or physiological sAβ, but partially degrade it via the secretion of insulin-degrading enzyme, which will be beneficial for understanding how sAβ is removed from the brain by microglia.Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

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