1alpha,25-dihydroxyvitamin D3 Interacts With Curcuminoids to Stimulate Amyloid-Beta Clearance by Macrophages of Alzheimer's Disease Patients

J Alzheimers Dis. 2009;17(3):703-17. doi: 10.3233/JAD-2009-1080.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism*
  • Cells, Cultured
  • Cholecalciferol / analogs & derivatives*
  • Cholecalciferol / pharmacology
  • Cognition Disorders / metabolism
  • Cognition Disorders / pathology
  • Curcumin / analogs & derivatives
  • Curcumin / chemistry
  • Curcumin / pharmacology*
  • Diarylheptanoids
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Macrophages / classification
  • Macrophages / drug effects*
  • Macrophages / metabolism*
  • Male
  • Middle Aged
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism
  • Peptide Fragments / metabolism*
  • Phagocytosis / drug effects
  • Protein Structure, Tertiary / genetics
  • Receptors, Calcitriol / genetics
  • Time Factors
  • Toll-Like Receptor 1 / genetics
  • Toll-Like Receptor 1 / metabolism
  • Transfection / methods

Substances

  • 1,25-dihydroxy-22-ene-vitamin D3
  • Amyloid beta-Peptides
  • Diarylheptanoids
  • Peptide Fragments
  • Receptors, Calcitriol
  • Toll-Like Receptor 1
  • amyloid beta-protein (1-42)
  • Cholecalciferol
  • bis(4-hydroxycinnamoyl)methane
  • N-Acetylglucosaminyltransferases
  • beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase
  • Curcumin