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Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer's Disease.


ABSTRACT: Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid ? has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid ? by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of proinflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid ? compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid ? to CD36. We have found seven molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid ?. By combining molecular docking and dynamics simulations, we suggested the second fatty acids binding site within the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as the binding pocket of these compounds. Free energy calculations predicted the nonpolar component as the driving force for the binding of these inhibitors. These molecules also inhibited the production of TNF-?, IL-6, and IL-1? by peritoneal macrophages stimulated with fibrils of amyloid ?. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.

SUBMITTER: Doens D 

PROVIDER: S-EPMC5737711 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

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