1alpha,25-dihydroxyvitamin D3 interacts with curcuminoids to stimulate amyloid-beta clearance by macrophages of Alzheimer's disease patients

Research output: Contribution to journalArticlepeer-review

Authors

  • Ava Masoumi
  • Ben Goldenson
  • Senait Ghirmai
  • Hripsime Avagyan
  • Justin Zaghi
  • Ken Abel
  • Xueying Zheng
  • Araceli Espinosa-Jeffrey
  • Michelle Mahanian
  • Phillip T Liu
  • Matthew Mizwickie
  • John Cashman
  • Milan Fiala

Colleges, School and Institutes

Abstract

Patients with Alzheimer's disease (AD) suffer from brain amyloidosis related to defective clearance of amyloid-beta (Abeta) by the innate immune system. To improve the innate immune system of AD patients, we studied immune stimulation of macrophages by 1alpha,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 Abeta 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.

Details

Original languageEnglish
Pages (from-to)703-17
Number of pages15
JournalJournal of Alzheimer's Disease
Volume17
Issue number3
Publication statusPublished - 2009

Keywords

  • Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Cells, Cultured, Cholecalciferol, Cognition Disorders, Curcumin, Dose-Response Relationship, Drug, Drug Interactions, Female, Gene Expression Regulation, Humans, Liver, Macrophages, Male, Middle Aged, N-Acetylglucosaminyltransferases, Peptide Fragments, Phagocytosis, Protein Structure, Tertiary, Receptors, Calcitriol, Time Factors, Toll-Like Receptor 1, Transfection

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