title: 1α,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients.
abstract: As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA, University of California-Los Angeles, CA 90095, USA. mmizwicki@mednet.ucla.edu
authors.forename: Mathew T
authors.initials: MT
authors.lastname: Mizwicki
authors.forename: Guanghao
authors.initials: G
authors.lastname: Liu
authors.forename: Milan
authors.initials: M
authors.lastname: Fiala
authors.forename: Larry
authors.initials: L
authors.lastname: Magpantay
authors.forename: James
authors.initials: J
authors.lastname: Sayre
authors.forename: Avi
authors.initials: A
authors.lastname: Siani
authors.forename: Michelle
authors.initials: M
authors.lastname: Mahanian
authors.forename: Rachel
authors.initials: R
authors.lastname: Weitzman
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Hayden
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rosenthal
authors.forename: Ilka
authors.initials: I
authors.lastname: Nemere
authors.forename: John
authors.initials: J
authors.lastname: Ringman
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); C118756:dihydroxy-vitamin D3; C518399:resolvin D1; D014807:Vitamin D; D004281:Docosahexaenoic Acids; D037342:Pertussis Toxin