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1,25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid- phagocytosis and inflammation in Alzheimer’s disease patients

Mizwicki, MT;Liu, G;Fiala, M;Magpantay, L;Sayre, J;Siani, A;Mahanian, M;Weitzman, R;Hayden, EY;Rosenthal, MJ;Nemere, I;Ringman, J;Teplow, DB;

As immune defects in amyloid- (A) phagocytosis and degradation underlie A deposition and inflammation in Alzheimer’s disease (AD) brain, better understanding of the relation between A 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: 1,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-A by AD macrophages and inhibited fibrillar A-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 NFB; 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 (sA) 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 effects. However, they both further increased the expression of IL1 in the group 1, s-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote A 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.