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

Article type: Research Article

Authors: Mizwicki, Mathew T.^{a; *} | Liu, Guanghao^a | Fiala, Milan^{a; *} | Magpantay, Larry^d | Sayre, James^b | Siani, Avi^a | Mahanian, Michelle^a | Weitzman, Rachel^a | Hayden, Eric Y.^c | Rosenthal, Mark J.^e | Nemere, Ilka^f | Ringman, John^c | Teplow, David B.^c

Affiliations: [a] Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA | [b] Department of Biostatistics, University of California School of Public Health, Los Angeles, CA, USA | [c] Mary S. Easton Center for Alzheimer's Disease Research at UCLA, Department of Neurology, Brain Research and Molecular Biology Institutes, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA | [d] Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, CA, USA | [e] Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA | [f] Department of Nutrition and Food Science, Utah State University, Logan, UT, USA

Correspondence: [*] Correspondence to: Milan Fiala and Mathew Mizwicki, 100 UCLA Medical Plaza, Suite 220, Los Angeles, CA 90095, USA. Tel.: +1 310 206 6392; Fax: +1 310 246 1321; E-mails: [email protected]; [email protected].

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.

Keywords: Alzheimer's disease, amyloid-β, 1α,25-dihydroxyvitamin D3, phagocytosis, resolvin D1

DOI: 10.3233/JAD-121735

Journal: Journal of Alzheimer's Disease, vol. 34, no. 1, pp. 155-170, 2013