1α,25-dihydroxyvitamin D₃ Interacts with Curcuminoids to Stimulate Amyloid-β Clearance by Macrophages of Alzheimer's Disease Patients

Article type: Research Article

Authors: Masoumi, Ava^a | Goldenson, Ben^a | Ghirmai, Senait^b | Avagyan, Hripsime^a | Zaghi, Justin^a | Abel, Ken^b | Zheng, Xueying^b | Espinosa-Jeffrey, Araceli^c | Mahanian, Michelle^a | Liu, Phillip T.^d | Hewison, Martin^a | Mizwicki, Matthew^e | Cashman, John^b | Fiala, Milan^{a; *}

Affiliations: [a] Department of Orthopaedic Surgery, UCLA School of Medicine, Los Angeles, CA, USA | [b] Human BioMolecular Research Institute, San Diego, CA, USA | [c] Department of Neurobiology, UCLA School of Medicine, Los Angeles, CA, USA | [d] Department of Medicine, UCLA School of Medicine, Los Angeles, CA, USA | [e] Department of Biochemistry, University of California, Riverside, Riverside, CA, USA

Correspondence: [*] Corresponding author: Milan Fiala, M.D., UCLA Orthopaedic Hospital Research Center, 615 Charles E. Young Drive South, Los Angeles, CA 90095-7358, USA. Tel.: +1 310 206 6392; E-mail: [email protected].

Abstract: Patients with Alzheimer's disease (AD) suffer from brain amyloidosis related to defective clearance of amyloid-β (Aβ) by the innate immune system. To improve the innate immune system of AD patients, we studied immune stimulation of macrophages by 1α,25(OH)2-vitamin D3(1,25D3) in combination with curcuminoids. AD patients' macrophages segregate into Type I (positively stimulated by curcuminoids regarding MGAT-III transcription) and Type II (not stimulated). In both Type I and Type II macrophages, 1,25D3 strongly stimulated Aβ phagocytosis and clearance while protecting against apoptosis. Certain synthetic curcuminoids in combination with 1,25D3 had additive effects on phagocytosis in Type I but not Type II macrophages. In addition, we investigated the mechanisms of 1,25D3 and curcuminoids in macrophages. The 1,25D3 genomic antagonist analog MK inhibited 1,25D3 but not curcuminoid effects, suggesting that 1,25D3 acts through the genomic pathway. In silico, 1,25D3 showed preferential binding to the genomic pocket of the vitamin D receptor, whereas bisdemethoxycurcumin showed preference for the non-genomic pocket. 1,25D3 is a promising hormone for AD immunoprophylaxis because in Type I macrophages combined treatment with 1,25D3 and curcuminoids has additive effects, and in Type II macrophages 1,25D3 treatment is effective alone. Human macrophages are a new paradigm for testing immune therapies for AD.

Keywords: Alzheimer's disease, amyloid-β, curcuminoids, 1α, 25-dihydroxyvitamin D₃, macrophages, MGAT-III, phagocytosis, vitamin D

DOI: 10.3233/JAD-2009-1080

Journal: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 703-717, 2009