Reducing amyloid beta peptide production through regulation of amyloid precursor protein dimerization
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Alzheimer’s disease is a progressive and irreversible neurodegenerative disorder characterized by the accumulation of neurotoxic Aβ peptides and subsequent onset of secondary neuropathological changes, including aggregation of hyperphosphorylated tau protein. Aβ peptides, produced through the successive actions of β- and γ-secretase in the amyloidogenic processing pathway of APP, aggregate into neurotoxic oligomeric Aβ and amyloid plaques. The reduction of Aβ peptide formation through the inhibition of β- and γ-secretase of the amyloidogenic pathway and the activation of α-secretase of the nonamyloidogenic pathway has been a primary focus of many recent therapeutic research studies. Alternative strategies include increasing Aβ peptide clearance from the cerebral cortex through both active and passive immunization. Although some of these potential treatment options for Alzheimer’s disease have shown promise, they carry a great deal of risk with a variety of unintended side effects. Moreover, there are currently no diseasemodifying drugs available to treat Alzheimer’s disease, as most therapeutics are targeted to treat symptoms of the disease rather than the disease itself. Recent studies suggest a link between APP dimerization and Aβ production. Compound Y, which inhibited APP dimerization, was discovered by Pauline So and her colleagues in the Abraham lab at Boston University and was shown to reduce Aβ production by lowering sAPPβ levels, suggesting that the inhibition of APP dimerization affects the β-secretase cleavage of APP. A kinase profiling assay revealed that compound Y10, an analog of compound Y, exhibited its action through the inhibition of receptor tyrosine kinase cKit. Interestingly, inhibition of cKit enhanced APP phosphorylation, suggesting that cKit indirectly affects APP. Known cKit interactors with potential to affect downstream APP phosphorylation were studied, leading to the discovery of Shp2, a tyrosine phosphatase directly linked to cKit signaling. After demonstrating that known Shp2 inhibitors increase APP phosphorylation and lower Aβ production, it was hypothesized that both cKit and Shp2 are involved in APP processing. The objective of the current study is to explore the potential for Shp2 as a novel therapeutic target in Alzheimer’s disease. Potential Shp2-inhibiting compounds, synthesized in collaboration with Dr. John Porco and his colleagues at the Center for Molecular Discovery at Boston University, were screened for their ability to inhibit Shp2 using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as a substrate. Five compounds were shown to significantly inhibit Shp2, and these compounds were subsequently tested in a dose-dependent manner to determine their potency. All five compounds compared favorably with the potency of a known Shp2 inhibitor. As a result, these five compounds have become lead candidates in the next stage of evaluation. With a growing aging population and an ever-increasing economic burden placed on global healthcare systems, there is a pressing need to develop a disease-modifying treatment for Alzheimer’s disease. This study contributes to the scientific knowledge behind Alzheimer’s disease and provides the necessary tools for the discovery of potential therapeutics.