Small molecule amyloid-beta protein precursor processing modulators lower amyloid-beta peptide levels via cKit signaling
Files
Accepted manuscript
Date
2019-01-01
Authors
Chen, Ci-Di
Zeldich, Ella
Khodr, Christina
Camara, Kaddy
Tung, Tze Yu
Lauder, Emma C.
Mullen, Patrick
Polanco, Taryn J.
Liu, Yen-Yu
Zeldich, Dean
Version
Accepted manuscript
OA Version
Citation
Ci-Di Chen, Ella Zeldich, Christina Khodr, Kaddy Camara, Tze Yu Tung, Emma C Lauder, Patrick Mullen, Taryn J Polanco, Yen-Yu Liu, Dean Zeldich, Weiming Xia, William E Van Nostrand, Lauren E Brown, John A Porco, Carmela R Abraham. 2019. "Small Molecule Amyloid-beta Protein Precursor Processing Modulators Lower Amyloid-beta Peptide Levels via cKit Signaling." JOURNAL OF ALZHEIMERS DISEASE, Volume 67, Issue 3, pp. 1089 - 1106 (18). https://doi.org/10.3233/JAD-180923
Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput screen of a compound library for inhibitors of AβPP dimerization, and identified a compound that reduces Aβ levels. In the present study, we have identified an analog, compound Y10, which also reduced Aβ. Initial kinase profiling assays identified the receptor tyrosine kinase cKit as a putative Y10 target. To elucidate the precise mechanism involved, AβPP phosphorylation was examined by IP-western blotting. We found that Y10 inhibits cKit phosphorylation and increases AβPP phosphorylation mainly on tyrosine residue Y743, according to AβPP751 numbering. A known cKit inhibitor and siRNA specific to cKit were also found to increase AβPP phosphorylation and lower Aβ levels. We also investigated a cKit downstream signaling molecule, the Shp2 phosphatase, and found that known Shp2 inhibitors and siRNA specific to Shp2 also increase AβPP phosphorylation, suggesting that the cKit signaling pathway is also involved in AβPP phosphorylation and Aβ production. We further found that inhibitors of both cKit and Shp2 enhance AβPP surface localization. Thus, regulation of AβPP phosphorylation by small molecules should be considered as a novel therapeutic intervention for AD.