PHAGO Publications

23/07/2019

Small Molecule Binding to Alzheimer’s Risk Factor CD33 Promotes Aβ Phagocytosis

iScience - Luke A. Miles, Stefan J. Hermans, Gabriela A.N. Crespi, Jonathan H. Gooi, Larissa Doughty, Tracy L. Nero, Jasmina Markulić, Andreas Ebneth, Berthold Wroblowski, Daniel Oehlrich, Andrés A. Trabanco, Marie-Laure Rives, Ines Royaux, Nancy C. Hancock, Michael W. Parker

Luke A. Miles, Stefan J. Hermans, Gabriela A.N. Crespi, Jonathan H. Gooi, Larissa Doughty, Tracy L. Nero, Jasmina Markulić, Andreas Ebneth, Berthold Wroblowski, Daniel Oehlrich, Andrés A. Trabanco, Marie-Laure Rives, Ines Royaux, Nancy C. Hancock, Michael W. Parker

https://doi.org/10.1016/j.isci.2019.07.023

 

Abstract

Polymorphism in the microglial receptor CD33 gene has been linked to late-onset Alzheimer’s disease (AD) and reduced expression of the CD33 sialic acid-binding domain confers protection. Thus, CD33 inhibition might be an effective therapy against disease progression. Lack of progress towards discovery of selective CD33 inhibitors has been hampered by the absence of an atomic resolution structure. We report here the crystal structures of CD33 alone and bound to a subtype-selective sialic acid mimetic called P22 and use them to identify key binding residues by site-directed mutagenesis and binding assays to reveal the molecular basis for its selectivity towards sialylated glycoproteins and glycolipids. We show that P22, when presented on microparticles, increases uptake of the toxic AD peptide, Aβ, into microglial cells. Thus, the sialic acid-binding site on CD33 is a promising pharmacophore for developing therapeutics that promote clearance of the Aβ peptide that is thought to cause AD.

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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.

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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.