Reducing amyloid beta peptide production through regulation of amyloid precursor protein dimerization
Embargo Date
2018-06-15
OA Version
Citation
Abstract
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.