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Published on: November 9, 2018
Small Molecule Decoy of Amyloid-β Aggregation Blocks Activation of Microglia-Like Cells
Sho Oasa1, Gefei Chen2, Marianne Schultzberg3
1Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Background:
Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in the brain are signatures of Alzheimer's disease (AD). Aggregates are also recognized by microglia, which in early phases may be protective and in later phases contribute to the pathology. We have identified several small molecules, decoys which interfere with Aβ oligomerization and induce other aggregation trajectories leading to aggregated macrostructures which are non-toxic.
Objective:
This study investigates whether the small-molecule decoys affect microglial activation in terms of cytokine secretion and phagocytosis of Aβ peptide.
Methods:
The effects of the decoys (NSC 69318, NSC 100873, NSC 16224) were analyzed in a model of human THP-1 monocytes differentiated to microglia-like cells. The cells were activated by Aβ40 and Aβ42 peptides, respectively, and after treatment with each decoy the secreted levels of pro-inflammatory cytokines and the Aβ phagocytosis were analyzed.
Results:
NSC16224, which generates a double-stranded aggregate of thin protofibrils, was found to block Aβ40- and Aβ42-induced increase in microglial secretion of pro-inflammatory cytokines. NSC 69318, selective for neurotoxicity of Aβ42, and NSC 100873 did not significantly reduce the microglial activation in terms of cytokine secretion. The uptake of Aβ42 was not affected by anyone of the decoys.
Conclusions:
Our findings open the possibility that the molecular decoys of Aβ aggregation may block microglial activation by Aβ40 and Aβ42 in addition to blocking neurotoxicity as shown previously.
Insights
Small-molecule decoys targeting amyloid-β (Aβ) aggregation may reduce Alzheimer's disease pathology by blocking microglial activation. One decoy, NSC16224, inhibited Aβ-induced pro-inflammatory cytokine release from microglia.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide aggregates.
- Microglia recognize Aβ aggregates, potentially contributing to AD pathology.
- Small-molecule decoys have been identified that interfere with Aβ oligomerization, forming non-toxic aggregates.
Purpose of the Study:
- To investigate the impact of small-molecule decoys on microglial activation.
- To assess the effects of decoys on cytokine secretion and Aβ phagocytosis by microglia.
Main Methods:
- Human THP-1 monocytes were differentiated into microglia-like cells.
- Cells were activated with Aβ40 and Aβ42 peptides in the presence of decoys (NSC 69318, NSC 100873, NSC 16224).
- Secreted pro-inflammatory cytokines and Aβ phagocytosis were analyzed.
Main Results:
- NSC16224 blocked the increase in pro-inflammatory cytokine secretion induced by Aβ40 and Aβ42.
- NSC 69318 and NSC 100873 did not significantly reduce microglial activation.
- Decoy treatment did not affect the uptake of Aβ42 by microglia.
Conclusions:
- Molecular decoys of Aβ aggregation show potential in blocking microglial activation.
- This mechanism may complement the previously demonstrated neuroprotective effects of these decoys.
