Genomic and nongenomic signaling induced by 1α,25(OH)2-vitamin D3 promotes the recovery of amyloid-β phagocytosis by Alzheimer's disease macrophages.
Brain clearance of amyloid-β (Aβ42) by innate immune cells is necessary for maintenance of normal brain function. Phagocytosis of soluble Aβ42 by Alzheimer's disease (AD) macrophages is defective, recovered in all "Type I and Type II" AD patients by 1α,25(OH)2-vitamin D3 (1,25D3) and blocked by the nuclear vitamin D receptor (VDR) antagonist (23S)-25-dehydro-1α(OH)-vitamin D3-26,23-lactone (MK). Bisdemethoxycurcumin (BDC) is a VDR ligand and additive with 1,25D3 in promoting Aβ42 phagocytosis by Type I, but not by Type II macrophages. Here, we define the following intracellular mechanisms regulated by 1,25D3 that are associated with recovery of phagocytosis and consistent with the selectivity of BDC: 1) 1,25D3 potentiates a 4,4-diisothiocyanostilbene-2,2-disulfonic acid-sensitive chloride channel (i.e., ClC-3) currents in both Type I and II AD macrophages, but curcumin only potentiates the currents in Type I cells; 2) 1,25D3 is particularly effective in upregulating ClC-3 mRNA expression in Type II peripheral blood mononuclear cells (PBMCs) while both 1,25D3 and the BDC analog, C180, upregulate VDR mRNA, repressed by Aβ42 in Type II PBMCs; and 3) 1,25D3-induced Aβ42 phagocytosis is attenuated by the calcium-dependent ClC-3 blocker, inositol 3,4,5,6-tetraphosphate (IP4), in both AD Types and by the MEK1/2 inhibitor U0126 only in Type II macrophages. VDR hydrogen/deuterium exchange coupled mass spectrometry and computational results show differences between the abilities of 1,25D3 and curcuminoids to stabilize VDR helices associated with the regulation of gene transcription. The structure-function results provide evidence that 1,25D3 activation of VDR-dependent genomic and nongenomic signaling, work in concert to recover dysregulated innate immune function in AD.
Department of Biochemistry, University of California, Riverside, CA 90095-3517, USA.
Mathew T
MT
Mizwicki
Danusa
D
Menegaz
Jun
J
Zhang
Antonio
A
Barrientos-Durán
Stephen
S
Tse
John R
JR
Cashman
Patrick R
PR
Griffin
Milan
M
Fiala
D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology*; D002117:Calcitriol / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D010587:Phagocytosis; D017433:Protein Structure, Secondary; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D002117:Calcitriol