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1α,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients.
- Source :
-
Journal of Alzheimer's disease : JAD [J Alzheimers Dis] 2013; Vol. 34 (1), pp. 155-70. - Publication Year :
- 2013
-
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.
- Subjects :
- Adolescent
Adult
Alzheimer Disease pathology
Amyloid beta-Peptides pharmacology
Apoptosis drug effects
Cells, Cultured
Child
Cytokines genetics
Cytokines metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors pharmacology
Female
Gene Expression Regulation drug effects
Humans
Male
Peptide Fragments pharmacology
Pertussis Toxin pharmacology
Phagocytosis drug effects
RNA, Messenger metabolism
Time Factors
Vitamin D metabolism
Young Adult
Alzheimer Disease complications
Amyloid beta-Peptides metabolism
Docosahexaenoic Acids metabolism
Inflammation etiology
Phagocytosis immunology
Vitamin D analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1875-8908
- Volume :
- 34
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of Alzheimer's disease : JAD
- Publication Type :
- Academic Journal
- Accession number :
- 23186989
- Full Text :
- https://doi.org/10.3233/JAD-121735