Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease

Jing Zhao, Xinyue Liu, Weiming Xia, Yingkai Zhang, Chunyu Wang

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number137
JournalFrontiers in Molecular Neuroscience
Volume13
DOIs
StatePublished - Aug 4 2020

Keywords

  • Alzheimer’s disease
  • amyloid-β
  • clinical trial
  • β-secretase inhibitor
  • γ-secretase inhibitors
  • γ-secretase modulator

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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