Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Aβ) 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 Aβ in the brain. Macrophages of most AD patients do not transport Aβ into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear Aβ from AD brain. After stimulation with Aβ, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes β-1,4-mannosyl-glycoprotein 4-β-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 Aβ 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 Aβ and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of Aβ 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.
Highlights
Alzheimer's disease (AD) is a major public health problem with a huge associated impact on individuals, families, the healthcare system, and society
The enhanced phagocytosis capabilities in the presence of bisdemethoxycurcumin was generally associated with increases in expression of MGAT3 and Toll-like receptor (TLR) genes in peripheral blood mononuclear cells (PBMCs) from individuals testing positive for AD
The results suggested that monocytes from control individuals were markedly more effective at clearing Aβ when co-cultured with brain tissue than monocytes from AD patients that were defective in Aβ clearance [11]
Summary
Alzheimer's disease (AD) is a major public health problem with a huge associated impact on individuals, families, the healthcare system, and society. The enhanced phagocytosis capabilities in the presence of bisdemethoxycurcumin was generally associated with increases in expression of MGAT3 and TLR genes in PBMCs from individuals testing positive for AD. As described more fully in a later section, treating PBMCs from control subjects with Aβ was associated with a relatively elevated expression of the gene MGAT3, and genes encoding TLRs. In contrast, and in general, monocytes from AD patients markedly down-regulate these same genes with the same treatment. Integrating the pathway information with microarray data from differently treated cells will allow the assembly and quantification of sets of genes that appear to be significantly over-represented among all known genes, and determine if those genes are related biologically In this way, we can determine which metabolic, biochemical, and transcriptional networks and pathways appear to be responsive to Aβ and curcumin treatments.
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