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 β has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid β 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 pro-inflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid β compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid β to CD36. We have found 7 molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid β. Molecular docking simulations have suggested the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as a target of these compounds. These molecules also inhibited the production of TNF-α, IL-6 and IL-1β by peritoneal macrophages stimulated with fibrils of amyloid β. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.

Tandem Deoxygenation/Halogenation of N‐Oxides Under Acylation Conditions: Scope and In Situ IR Spectroscopic Study

“…However, the open‐chain γ‐amino acid derivative 14a was prepared by an inverted sequence of bonds reduction in 11a : firstly the cleavage of N–O bond in 11a was accomplished with VCl 3 /Zn system followed by stereoselective hydrogenation of the C=C bond in the resulting enamine on the second stage. Thus, depending on the reagents used, 2 H ‐1,2‐oxazines 11 can serve as precursors to either open‐chain or cyclic γ‐amino acid derivatives bearing up to four contiguous stereocenters.…”

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…AD is also associated with elevated microglia-induced neuroinflammation, increases in proinflammatory cytokines, and upregulated expression of phagocytic receptors in white matter microglia (Zheng et al, 2016). One receptor, CD36, promotes both pro-inflammatory and oxidative pathways upon binding to ligands, including lipids and Aβ (Doens et al, 2017). Overexpression may lead to dysregulated inflammation and increased oxidative stress, a biomarker of the inflammatory response, and AD (Park et al, 2014;Koizumi et al, 2016).…”

CD36 tango in cancer: signaling pathways and functions

“…CD36 also functions in innate immunity as a pattern-recognition receptor (PRR) by recognizing exogenous materials such as red blood cells infected by Plasmodium falciparum and the cell-wall components of staphylococcus and mycobacterium 81. Moreover, CD36 recognizes endogenous ligands: CD36 on DCs can recognize apoptotic cells and cross-present antigens to T cells 82, and CD36 on macrophages can bind to β-amyloid peptides 83, apoptotic cells 84, AOPPs 85, and AGEs 86.…”