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      Heme and hemoglobin suppress amyloid β–mediated inflammatory activation of mouse astrocytes

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          Abstract

          Glial immune activity is a key feature of Alzheimer's disease (AD). Given that the blood factors heme and hemoglobin (Hb) are both elevated in AD tissues and have immunomodulatory roles, here we sought to interrogate their roles in modulating β-amyloid (Aβ)-mediated inflammatory activation of astrocytes. We discovered that heme and Hb suppress immune activity of primary mouse astrocytes by reducing expression of several proinflammatory cytokines ( e.g. RANTES (regulated on activation normal T cell expressed and secreted)) and the scavenger receptor CD36 and reducing internalization of Aβ(1–42) by astrocytes. Moreover, we found that certain soluble (>75-kDa) Aβ(1–42) oligomers are primarily responsible for astrocyte activation and that heme or Hb association with these oligomers reverses inflammation. We further found that heme up-regulates phosphoprotein signaling in the phosphoinositide 3-kinase (PI3K)/Akt pathway, which regulates a number of immune functions, including cytokine expression and phagocytosis. The findings in this work suggest that dysregulation of Hb and heme levels in AD brains may contribute to impaired amyloid clearance and that targeting heme homeostasis may reduce amyloid pathogenesis. Altogether, we propose heme as a critical molecular link between amyloid pathology and AD risk factors, such as aging, brain injury, and stroke, which increase Hb and heme levels in the brain.

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          Author and article information

          Journal
          J Biol Chem
          J. Biol. Chem
          jbc
          jbc
          JBC
          The Journal of Biological Chemistry
          American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
          0021-9258
          1083-351X
          20 July 2018
          5 June 2018
          : 293
          : 29
          : 11358-11373
          Affiliations
          From the []Wallace H. Coulter Department of Biomedical Engineering,
          the [§ ]School of Chemistry and Biochemistry,
          the []Parker H. Petit Institute for Bioengineering and Bioscience, and
          the []George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332
          Author notes
          [3 ] To whom correspondence may be addressed: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332. Tel.: 404-385-1428; E-mail: amit.reddi@ 123456chemistry.gatech.edu .
          [4 ] To whom correspondence may be addressed: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta GA, 30332. Tel.: 404-385-4465; E-mail: levi.wood@ 123456me.gatech.edu .
          [1]

          Both authors contributed equally to this work.

          [2]

          Recipient of the Georgia Tech President's Undergraduate Research Award.

          Edited by Paul E. Fraser

          Author information
          https://orcid.org/0000-0002-2255-7331
          Article
          PMC6065172 PMC6065172 6065172 RA117.001050
          10.1074/jbc.RA117.001050
          6065172
          29871926
          d53717e0-068b-4ff1-b63c-1ed6bb632170
          © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
          History
          : 20 November 2017
          : 24 May 2018
          Funding
          Funded by: Georgia Institute of Technology (Georgia Tech) , open-funder-registry 10.13039/100006778;
          Award ID: New Faculty Startup
          Award ID: New Faculty Startup
          Award ID: President's Undergraduate Research Award
          Funded by: Georgia Tech Parker H. Petit Institute for Bioengineering and Bioscience (Petit Institute) , open-funder-registry 10.13039/100008267;
          Award ID: Seed Grant
          Funded by: Blanchard Faculty Fellowship
          Award ID: N/A
          Funded by: National Science Foundation (NSF) , open-funder-registry 10.13039/100000001;
          Award ID: MCB 1552791
          Funded by: HHS National Institutes of Health (NIH) , open-funder-registry 10.13039/100000002;
          Award ID: ES025661
          Categories
          Molecular Bases of Disease

          Alzheimer disease,hemoglobin,heme,astrocyte,amyloid-beta (AB)

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