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γ-Secretase in Alzheimer's disease

  • 작성자

    Ji Yeun Hur
  • 작성일자

    2022-07-20
  • 조회수

    234
Ji Yeun Hur( hurj@mskcc.org )
2019-presentSenior Research Scientist, Chemical Biology Program, Memorial Sloan Kettering Cancer Center, USA
2011-2019Research Fellow and Research Associate, Chemical Biology Program, Memorial Sloan Kettering Cancer Center, USA
2010-2011Postdoctoral Fellow, Dept. of Neurobiology, Care Sciences and Society, Karolinska Institutet, Sweden
2004-2010PhD, Dept. of Neurobiology, Care Sciences and Society, Karolinska Institutet, Sweden
2003-2004Stockholm Graduate School of Molecular Life Sciences, Sweden
2001-2003MS, Neuroscience Graduate Program, Graduate School of Medicine, Ajou University, Korea
1997-2001BS, Dept. of Biological Sciences, Ajou University, Korea

γ-Secretase in Alzheimer's disease

Alzheimer's disease (AD) is caused by synaptic and neuronal loss in the brain. One of the characteristic hallmarks of AD is senile plaques containing amyloid β-peptide (Aβ). Aβ is produced from amyloid precursor protein (APP) by sequential proteolytic cleavages by β-secretase and γ-secretase, and the polymerization of Aβ into amyloid plaques is thought to be a key pathogenic event in AD. Since γ-secretase mediates the final cleavage that liberates Aβ, γ-secretase has been widely studied as a potential drug target for the treatment of AD. γ-Secretase is a transmembrane protein complex containing presenilin, nicastrin, Aph-1, and Pen-2, which are sufficient for γ-secretase activity. γ-Secretase cleaves >140 substrates, including APP and Notch. Previously, γ-secretase inhibitors (GSIs) were shown to cause side effects in clinical trials due to the inhibition of Notch signaling. Therefore, more specific regulation or modulation of γ-secretase is needed. In recent years, γ-secretase modulators (GSMs) have been developed. To modulate γ-secretase and to understand its complex biology, finding the binding sites of GSIs and GSMs on γ-secretase as well as identifying transiently binding γ-secretase modulatory proteins have been of great interest. In this review, decades of findings on γ-secretase in AD are discussed.

Exp. Mol. Med. 2022 Apr;54(4):433-446. doi: 10.1038/s12276-022-00754-8. Epub 2022 Apr