Molecular basis of selective amyloid-β degrading enzymes in Alzheimer’s disease

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The accumulation of the small 42-residue long peptide amyloid-β (Aβ) has been proposed as a major trigger for the development of Alzheimer's disease (AD). Within the brain, the concentration of Aβ peptide is tightly controlled through production and clearance mechanisms. Substantial experimental evidence now shows that reduced levels of Aβ clearance are present in individuals living with AD. This accumulation of Aβ can lead to the formation of large aggregated amyloid plaques—one of two detectable hallmarks of the disease. Aβ-degrading enzymes (ADEs) are major players in the clearance of Aβ. Stimulating ADE activity or expression, in order to compensate for the decreased clearance in the AD phenotype, provides a promising therapeutic target. It has been reported in mice that upregulation of ADEs can reduce the levels of Aβ peptide and amyloid plaques—in some cases, this led to improved cognitive function. Among several known ADEs, neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), insulin degrading enzyme (IDE) and angiotensin-1 converting enzyme (ACE) from the zinc metalloprotease family have been identified as important. These ADEs have the capacity to digest soluble Aβ which, in turn, cannot form the toxic oligomeric species. While they are known for their amyloid degradation, they exhibit complexity through promiscuous nature and a broad range of substrates that they can degrade. This review highlights current structural and functional understanding of these key ADEs, giving some insight into the molecular interactions that leads to the hydrolysis of peptide substrates, the crucial tasks performed by them and the potential for therapeutic use in the future.

Original languageEnglish
JournalFEBS Journal
Early online date25 Aug 2023
Publication statusE-pub ahead of print - 25 Aug 2023

Bibliographical note

Funding Information:
The authors would like to thank all of those scientists whose fruitful research has contributed in any way to the elucidation of the role of amyloid degrading enzymes in Alzheimer's disease. JZ is supported by a Heather Corrie postgraduate studentship from the Alzheimer's Society (UK) awarded to KRA and VS [grant number – 551 (AS‐PhD‐19b‐011)]. SJM was supported by a postgraduate studentship from the Alzheimer's Society (UK) awarded to KRA and VS [grant number – 286 (AS‐PhD2015b‐006)].


  • Alzheimer's disease
  • Amyloid-degrading enzyme
  • Aβ-peptide
  • molecular structure
  • therapeutic use

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Cell Biology


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