Immune defects in Alzheimer's disease: new medications development

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (A beta) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of A beta in the brain. Macrophages of most AD patients do not transport A beta into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear A beta from AD brain. After stimulation with A beta, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, and Toll-like receptor (TLR) genes. Monocytes of AD patients generally down-regulate these genes. A commonly used, naturally occurring material from a spice that enhances certain key functions defective in cells of innate immunity of many AD patients has shown epidemiologic rationale for use in AD treatment. Bisdemethoxycurcumin, a natural curcumin, is a minor constituent of turmeric (curry), and it enhances phagocytosis and clearance of A beta in cells from most AD patients. We confirmed the effectiveness of a synthetic version of the same compound. In mononuclear cells of most AD patients, bisdemethoxycurcumin enhanced defective phagocytosis of A beta and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of A beta in mononuclear cells suggests the promise of enhanced effectiveness compared to curcuminoid mixtures. Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy.