Brain clearance of amyloid-Î² (AÎ²42) by innate immune cells is necessary for maintenance of normal brain function. Phagocytosis of soluble AÎ²42 by Alzheimer's disease (AD) macrophages is defective, recovered in all "Type I and Type II" AD patients by 1Î±,25(OH)2-vitamin D3 (1,25D3) and blocked by the nuclear vitamin D receptor (VDR) antagonist (23S)-25-dehydro-1Î±(OH)-vitamin D3-26,23-lactone (MK). Bisdemethoxycurcumin (BDC) is a VDR ligand and additive with 1,25D3 in promoting AÎ²42 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 AÎ²42 in Type II PBMCs; and 3) 1,25D3-induced AÎ²42 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. (http://www.j-alz.com/issues/29/vol29-1.html)
In other words: "Vitamin D3 and curcumin work together to clear deadly brain plaques." Vitamin D3 and curcumin synergistically clear brain tangles to help prevent Alzheimer's dementia. I'll have to remember that.