Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin.
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-beta (Abeta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Abeta into endosomes and lysosomes, and AD monocytes do not efficiently clear Abeta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Abeta to endosomes and lysosomes, and monocytes of these subjects clear Abeta in AD brain sections. Upon Abeta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-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 Abeta 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 Abeta 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 Abeta, 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.
Fiala
Milan
M
Department of Medicine, Greater Los Angeles Veterans Affairs Medical Center, and School of Medicine, University of California-Los Angeles, CA 90095, USA. fiala@mednet.ucla.edu
Liu
Philip T
PT
Espinosa-Jeffrey
Araceli
A
Rosenthal
Mark J
MJ
Bernard
George
G
Ringman
John M
JM
Sayre
James
J
Zhang
Laura
L
Zaghi
Justin
J
Dejbakhsh
Sheila
S
Chiang
Ben
B
Hui
James
J
Mahanian
Michelle
M
Baghaee
Anita
A
Hong
Pamela
P
Cashman
John
J
D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002450:Cell Communication; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D036381:Diarylheptanoids; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007167:Immunotherapy; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D014176:Protein Biosynthesis; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D051193:Toll-Like Receptors / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
D016229:Amyloid beta-Peptides; D036381:Diarylheptanoids; D034741:RNA, Small Interfering; D051193:Toll-Like Receptors; C034786:bisdemethoxycurcumin; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase; D003474:Curcumin