Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling

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.

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

“…Treatment with SHP2 inhibitors or cKit inhibitors enhanced the phosphorylation of amyloid-β protein precursor, thereby reducing the accumulation of amyloid-β in neuronal cells. 76 SHP2 also interacted with tau protein to form an SHP2-tau complex in neuronal cells. The formation of this complex was associated with the activation of SHP2 and the phosphorylation of tau.…”

Receptor for advanced glycation end products up‐regulation in cerebral endothelial cells mediates cerebrovascular‐related amyloid β accumulation after Porphyromonas gingivalis infection

“…The prevalence of AD continues to grow because of the increase in the aging population (Hodson, 2018). As the major pathological marker of AD brain, amyloid β protein (Aβ), a polypeptide consisting of 39–43 acid residues, is proteolytically generated by cleavage of amyloid precursor protein (Chen et al, 2019). Aβ accumulation in and around the cerebral vasculature, known as cerebral amyloid angiopathy (CAA), has been found in more than 80% of AD patients (Kovari, Herrmann, Hof, & Bouras, 2013).…”

Effects of probiotics supplementation on dementia and cognitive impairment: A systematic review and meta-analysis of preclinical and clinical studies

“…The gold treatment is cholinesterase inhibitors, which provide limited short-term cognitive benefits, whilst their clinical value remains a matter of controversy, considering the risk of side effects (Tricco et al, 2013;Hill et al, 2017). Indeed, the regulation of Amyloid-β protein precursor (AβPP) phosphorylation by small molecules is a novel therapeutic intervention for AD (Chen et al, 2019) . However, several studies have shown a reduction in Aβ load in the brain, but with the lack of beneficial effects on cognitive outcome measures, as well as impaired brain function (van der Kant, Goldstein, & Ossenkoppele, 2020).…”