Aβ-Degrading Enzymes: Potential for Treatment of Alzheimer Disease

Research output: Contribution to journalReview article (Academic Journal)

174 Citations (Scopus)

Abstract

There is increasing evidence that deficient clearance of β-amyloid (Aβ) contributes to its accumulation in late-onset Alzheimer disease (AD). Several Aβ-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce Aβ levels and protect against cognitive impairment in mouse models of AD. The activity of several Aβ-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the buildup of Aβ. The age- and disease-related changes in expression of more recently recognized Aβ-degrading enzymes (e.g. NEP-2 and cathepsin B) remain to be investigated, and there is strong evidence that reduced NEP activity contributes to the development of cerebral amyloid angiopathy. Regardless of the role of Aβ-degrading enzymes in the development of AD, experimental data indicate that increasing the activity of these enzymes (NEP in particular) has therapeutic potential in AD, although targeting their delivery to the brain remains a major challenge. The most promising current approaches include the peripheral administration of agents that enhance the activity of Aβ-degrading enzymes and the direct intracerebral delivery of NEP by convection-enhanced delivery. In the longer term, genetic approaches to increasing the intracerebral expression of NEP or other Aβ-degrading enzymes may offer advantages.
Translated title of the contributionAβ-Degrading Enzymes: Potential for Treatment of Alzheimer Disease
Original languageEnglish
Pages (from-to)944 - 959
Number of pages17
JournalJournal of Neuropathology and Experimental Neurology
Volume70
Issue number11
DOIs
Publication statusPublished - Nov 2011

Bibliographical note

Publisher: Lippincott Williams and Wilkins

Keywords

  • Animals
  • Humans
  • Insulysin
  • Alzheimer Disease
  • Disease Models, Animal
  • Genetic Therapy
  • Mice
  • Neprilysin
  • Thiorphan
  • Mice, Transgenic
  • Microglia
  • Protease Inhibitors
  • Glycopeptides
  • Amyloid beta-Peptides
  • Stem Cell Transplantation

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