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- (A) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport A into endosomes and lysosomes, and AD monocytes do not efficiently clear A from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport A to endosomes and lysosomes, and monocytes of these subjects clear A in AD brain sections. Upon A stimulation, mononuclear cells of normal subjects up-regulate the transcription of -1,4-mannosyl-glycoprotein 4--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 A 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 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, 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.amyloid- ͉ phagocytosis ͉ endocytosis ͉ MGAT3 siRNA A ccording to the amyloid- (A) hypothesis, amyloidosis occurring in the brain of patients with Alzheimer's disease (AD) by fibrillar A 1-42 and 1-40 (1) and A oligomers (2) is a leading cause of neurodegeneration in AD (3). Macrophages and microglia are the innate immune cells responsible for clearance of pathogens and waste products. We have shown that blood-borne monocyte/ macrophages of AD patients migrate across the blood-brain barrier into AD brain but are defective in clearance of A in neuritic plaques (4), and they overexpress cyclooxygenase-2 and inducible NO synthase (4). Resident microglia in AD brain display markers of inflammation (5, 6), phagocytosis (7), and proinflammatory but not prophagocytic genes (8). However, most microglia invading A plaques in transgenic mouse models are bone marrow-derived, not resident microglia (9). Thus, the brains of AD patients and transgenic mice seem to display inflammatory responses by microglia and defective A clearance by blood-borne macrophages. Consequently, the defective innate immune system of AD patients might be a culprit in brain amyloidosis leading to brain inflammation.The mechanisms of neurodegeneration produced by abnormally folded proteins, A, and phosphorylated remain an enigma (10).The pathogenesis of neurodegeneration in AD involves the impact of polymorphic proteins, such as amyloid precursor...
Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-β (1-42) (Aβ) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Aβ plaques [5]. The natural product curcuminoids enhanced brain clearance of Aβ in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Aβ uptake using fluorescence and confocal microscopy. At baseline, the intensity of Aβ uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. After treatment of macrophages with curcuminoids, Aβ uptake by macrophages of three of the six AD patients was significantly (P < 0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain.
This project was made possible by Animals Asia's established relationships with the Traditional Medical Association, local government officials, and the residents of our study site. It is thanks to AA that our team, as foreigners, had permission to conduct this research, building upon previously established trusted relationships in the community. Thank you especially to the following AA staff members who played key roles in making this work possible: Bendixsen Tuan (director),
Technological resources have expanded the goal of education from individual knowledge acquisition to include the development of critical thinking, communication, and collaboration (Griffin, McCaw, Care, 2012; Van Roekel, 2014). This shift requires a reevaluation of what students learn (e.g. content versus skills) and how students learn in formal education settings (Saavedra & Opfer, 2012). Thus, there is a critical need to find ways to create environments that enable embodied, enactive, extended, and embedded learning and develop critical thinking, communication, collaboration and creativity. MIT’s Education Arcade and the MIT Game Lab are exploring ways to meet this need by developing a cross-platform, collaborative educational game with a conceptual focus on cellular biology and a developmental focus on 21st century skills. To this end, we are creating learning environments that incorporate collaborative problem solving that are connected across different contexts.
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