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Glycoengineering artificial receptors for microglia to phagocytose Aβ aggregates

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Abstract

Oligomeric and fibrillar amyloid-β (Aβ) are principally internalized via receptor-mediated endocytosis (RME) by microglia, the main scavenger of Aβ in the brain. Nevertheless, the inflammatory cascade will be evoked after vast Aβ aggregate binding to pattern recognition receptors on the cell membrane, which then significantly decreases the expression of these receptors and further deteriorate Aβ deposition. This vicious circle will weaken the ability of microglia for Aβ elimination. Herein, a combination of metabolic glycoengineering and self-triggered click chemistry is utilized to engineer microglial membranes with ThS as artificial Aβ receptors to promote microglia to phagocytose Aβ aggregates. Additionally, to circumvent the undesirable immune response during the process of the bioorthogonal chemistry reaction and Aβ-microglial interaction, Mn-porphyrin metal–organic frameworks (Mn-MOFs) with superoxide dismutase (SOD) and catalase (CAT) mimic activity are employed to carry N-azidoacetylmannosamine (AcManNAz) and eradicate over-expressed reactive oxygen species (ROSs). The artificial Aβ receptors independent of a signal pathway involved in immunomodulation as well as Mn-MOFs with antioxidant properties can synergistically promote the phagocytosis and clearance of Aβ with significantly enhanced activity and negligible adverse effects. The present study will not only provide valuable insight into the rational design of the microglial surface engineering strategy via bioorthogonal chemistry, but also hold great potential for other disease intervention associated with receptor starvation.

Graphical abstract: Glycoengineering artificial receptors for microglia to phagocytose Aβ aggregates

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Supplementary files

Article information


Submitted
29 Dec 2020
Accepted
22 Feb 2021
First published
23 Feb 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021, Advance Article
Article type
Edge Article

Glycoengineering artificial receptors for microglia to phagocytose Aβ aggregates

D. Yu, C. Liu, H. Zhang, J. Ren and X. Qu, Chem. Sci., 2021, Advance Article , DOI: 10.1039/D0SC07067J

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