2. Academic Validation
  3. Targeting Amyloidogenic Processing of APP in Alzheimer's Disease

Targeting Amyloidogenic Processing of APP in Alzheimer's Disease

  • Front Mol Neurosci. 2020 Aug 4;13:137. doi: 10.3389/fnmol.2020.00137.
Jing Zhao 1,  Xinyue Liu 1,  Weiming Xia 2 3,  Yingkai Zhang 4,  Chunyu Wang 1 5 6
Affiliations

Affiliations

  • 1 Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United States.
  • 2 Geriatric Research Education Clinical Center, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA, United States.
  • 3 Department of Pharmacology and Experimental Therapeutics, School of Medicine, Boston University, Boston, MA, United States.
  • 4 Department of Chemistry, New York University, New York, NY, United States.
  • 5 Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY, United States.
  • 6 Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY, United States.
PMID: 32848600 DOI: 10.3389/fnmol.2020.00137
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.

Keywords

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

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