1α,25-Dihydroxyvitamin D3 and Resolvin D1 Retune the Balance between Amyloid-β Phagocytosis and Inflammation in Alzheimer's Disease Patients

As immune defects in amyloid-beta (A beta) phagocytosis and degradation underlie A beta deposition and inflammation in Alzheimer's disease (AD) brain, better understanding of the relation between A beta 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: 1 alpha,25(OH)(2)-vitaminD(3) (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-A beta by AD macrophages and inhibited fibrillar A beta-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 NF kappa B; 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 A beta (sA beta) 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 sA beta effects. However, they both further increased the expression of IL1 in the group 1, sA beta-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote A beta phagocytosis, and suggest that low vitamin D-3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.