TY - JOUR
T1 - Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease
AU - Zhao, Jing
AU - Liu, Xinyue
AU - Xia, Weiming
AU - Zhang, Yingkai
AU - Wang, Chunyu
N1 - Publisher Copyright:
© Copyright © 2020 Zhao, Liu, Xia, Zhang and Wang.
PY - 2020/8/4
Y1 - 2020/8/4
N2 - Alzheimer’s disease (AD) is the most common type of senile dementia, characterized by neurofibrillary tangle and amyloid plaque in brain pathology. Major efforts in AD drug were devoted to the interference with the production and accumulation of amyloid-β peptide (Aβ), which plays a causal role in the pathogenesis of AD. Aβ is generated from amyloid precursor protein (APP), by consecutive cleavage by β-secretase and γ-secretase. Therefore, β-secretase and γ-secretase inhibition have been the focus for AD drug discovery efforts for amyloid reduction. Here, we review β-secretase inhibitors and γ-secretase inhibitors/modulators, and their efficacies in clinical trials. In addition, we discussed the novel concept of specifically targeting the γ-secretase substrate APP. Targeting amyloidogenic processing of APP is still a fundamentally sound strategy to develop disease-modifying AD therapies and recent advance in γ-secretase/APP complex structure provides new opportunities in designing selective inhibitors/modulators for AD.
AB - Alzheimer’s disease (AD) is the most common type of senile dementia, characterized by neurofibrillary tangle and amyloid plaque in brain pathology. Major efforts in AD drug were devoted to the interference with the production and accumulation of amyloid-β peptide (Aβ), which plays a causal role in the pathogenesis of AD. Aβ is generated from amyloid precursor protein (APP), by consecutive cleavage by β-secretase and γ-secretase. Therefore, β-secretase and γ-secretase inhibition have been the focus for AD drug discovery efforts for amyloid reduction. Here, we review β-secretase inhibitors and γ-secretase inhibitors/modulators, and their efficacies in clinical trials. In addition, we discussed the novel concept of specifically targeting the γ-secretase substrate APP. Targeting amyloidogenic processing of APP is still a fundamentally sound strategy to develop disease-modifying AD therapies and recent advance in γ-secretase/APP complex structure provides new opportunities in designing selective inhibitors/modulators for AD.
KW - Alzheimer’s disease
KW - amyloid-β
KW - clinical trial
KW - β-secretase inhibitor
KW - γ-secretase inhibitors
KW - γ-secretase modulator
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U2 - 10.3389/fnmol.2020.00137
DO - 10.3389/fnmol.2020.00137
M3 - Review article
AN - SCOPUS:85089806886
SN - 1662-5099
VL - 13
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 137
ER -