Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 70, Issue 11, Pages 944-959Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e3182345e46
Keywords
A beta-degrading enzymes; Alzheimer disease treatment; Cathepsin B; Convection-enhanced delivery; Mouse models; Neprilysin
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Funding
- Alzheimer's Research UK
- James Tudor Foundation
- Royal College of Surgeons of England
- EPSRC [EP/G061866/1] Funding Source: UKRI
- Alzheimers Research UK [ART-RF2008-2] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/G061866/1] Funding Source: researchfish
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There is increasing evidence that deficient clearance of beta-amyloid (A beta) contributes to its accumulation in late-onset Alzheimer disease (AD). Several A beta-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce A beta levels and protect against cognitive impairment in mouse models of AD. The activity of several A beta-degrading enzymes rises with age and increases still further in AD, perhaps as a physiological response to minimize the buildup of A beta. The age- and disease-related changes in expression of more recently recognized A beta-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 A beta-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 A beta-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 A beta-degrading enzymes may offer advantages.
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