Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

doi:10.1073/pnas.0701267104

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

*Department of Medicine, Greater Los Angeles Veteran's Affairs Medical Center, and
Departments of ^‡Medicine, Microbiology, Immunology and Molecular Genetics,
^§Neurobiology, and
^‖Neurology, University of California School of Medicine, Los Angeles, CA 90095;
^¶Division of Oral Biology, University of California School of Dentistry, Los Angeles, CA 90095;
**Department of Biostatistics, University of California School of Public Health, Los Angeles, CA 90095; and
^††Human BioMolecular Research Institute, San Diego, CA 02121

Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA, and approved June 15, 2007 (received for review February 15, 2007)

Abstract

We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-β (Aβ) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Aβ into endosomes and lysosomes, and AD monocytes do not efficiently clear Aβ from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Aβ to endosomes and lysosomes, and monocytes of these subjects clear Aβ in AD brain sections. Upon Aβ stimulation, mononuclear cells of normal subjects up-regulate the transcription of β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Aβ may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon Aβ stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of Aβ, the transcription of MGAT3 and TLRs, and the translation of TLR2–4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.

Footnotes

^†To whom correspondence should be addressed. E-mail: fiala{at}mednet.ucla.edu
Author contributions: M.F. designed research; P.T.L., A.E.-J., L.Z., J.Z., S.D., B.C., J.H., M.M., A.B., and J.C. performed research; M.F., P.T.L., A.E.-J., M.J.R., G.B., J.M.R., J.S., M.M., A.B., P.H., and J.C. analyzed data; and M.F. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0701267104/DC1.
Abbreviations:

AD,

Alzheimer's disease;

Aβ,

amyloid-β;

TLR,

Toll-like receptor;

APP,

amyloid precursor protein;

PBMC,

peripheral blood mononuclear cell;

IOD,

integrated optical density;

qPCR,

quantitative PCR;

CT,

cycle threshold;

PE,

postexposure.