title: Aβ-degrading enzymes: potential for treatment of Alzheimer disease.
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.
authors: Dementia Research Group, Institute of Clinical Neurosciences, Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, UK. scott.miners@bristol.ac.uk
authors: James Scott
authors: JS
authors: Miners
authors: Neil
authors: N
authors: Barua
authors: Patrick Gavin
authors: PG
authors: Kehoe
authors: Steven
authors: S
authors: Gill
authors: Seth
authors: S
authors: Love
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D007339:Insulysin / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D033581:Stem Cell Transplantation / Q000379:methods; D015244:Thiorphan / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D006020:Glycopeptides; D011480:Protease Inhibitors; D015244:Thiorphan; D015260:Neprilysin; D007339:Insulysin; C008890:phosphoramidon