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.

Interleukin-10 Production in Response to Amyloid-β Differs between Slow and Fast Decliners in Patients with Alzheimer’s Disease

“…In accordance with our findings, some authors have reported an increase of IL-10 and IL-1ra, which should balance the higher in vitro production of pro-inflammatory cytokines [28,29]. However, some studies demonstrated a reduction of both pro-and antiinflammatory cytokines [30,31], suggesting a general impairment of immune functions in AD.…”

“…Ex vivo, LPS-and A␤-induced IL-10 production by PBMCs of AD patients and age-matched controls. PBMCs (3.10 6 cells / ml) from AD patients (n = 30) and age-matched controls (n = 18) were cultured either in complete medium alone (open symbol), supplemented with 1 ng/ml of LPS (full symbol, A) during two days or supplemented with a pool of three A␤ peptides: 1 g/ml of fragment (1-16), 10 g/ml of fragment (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and 25 g/ml of fragment (1-40) (full symbol, B) during five days. Results have been showed as scatter plot and the median value is indicated by a black plain line.…”

“…Blood from all individuals was collected at the same time in the morning and employed for biochemical tests and PBMCs isolation. PBMCs were cultured in medium, medium+LPS (1 ng/ml), or medium+pool of three A␤ peptides: 1 g/ml of fragment (1-16), 10 g/ml of fragment (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), and 25 g/ml of fragment (1-40) (Innovagen, Lund, Sweden). IL-10 production was measured with ELISA (Ready-SET-Go!…”

Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study

“…LXA 4 , and its analog aspirin-triggered LXA 4 , have also been shown to ameliorate the detrimental effects of A ␤ in vitro and in vivo ( 17,18,55 ), probably by increasing phagocytosis, downregulating proinfl ammatory signaling, and upregulating antiinflammatory cytokine production ( 11 ). RvD1 was also reported to enhance phagocytosis by macrophages ( 56 ). Thus, n-3 FA supplementation may favor the capacity of homeostatic functions to handle overabundance of A ␤ , as shown by preserved plasma TTR levels, SPM levels released by PBMCs, and an increased phagocytosis of A ␤ by microglia upon exposure to DHA and EPA in vitro ( 57 ).…”

Role of n-3 PUFAs in inflammationviaresolvin biosynthesis

“…The importance of the resolution pathway in maintaining normal cognition is suggested by the highlighted positive correlation between Mini-Mental State of Examination (MMSE) and the levels of RvD1 in the cerebrospinal fluid, suggesting that resolution can inhibit Alzheimer disease-related cognitive decline. Other studies published data reporting that a supplementation in n-3 PUFAs in patients with minor cognitive impairment increases RvD1 in macrophages (Fiala et al, 2015) and in vitro RvD1 with vitamin D promotes Aβ-phagocytosis in isolated Alzheimer's patient macrophages (Mizwicki et al, 2013). A study of Harrison et al (2015) demonstrates that RvE1, administered intraperitoneally for consecutive days, decreases the traumatic brain injury-induced activation of microglia.…”