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 (A beta) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport A beta into endosomes and lysosomes, and AD monocytes do not efficiently clear A beta from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport A beta to endosomes and lysosomes, and monocytes of these subjects clear A beta in AD brain sections. Upon A beta stimulation, mononuclear cells of normal subjects up-regulate the transcription of beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransf erase (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 A beta 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 A beta 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 A beta, 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 immumotherapy.