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), endothelin-converting enzyme (ECE), and angiotensin-converting enzyme (ACE) reduce Aβ levels and protect against cognitive impairment in mouse models of AD. In post-mortem human brain tissue we have found that the activity of these Aβ-degrading enzymes rise with age and increases still further in AD, perhaps as a physiological response that helps to minimize the build-up of Aβ. ECE-1/-2 and ACE are also rate-limiting enzymes in the production of endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictors, increases in the levels of which are likely to contribute to reduced blood flow in AD. This review considers the possible interdependence between Aβ-degrading enzymes, ischemia and Aβ in AD: ischemia has been shown to increase Aβ production both in vitro and in vivo, whereas increased Aβ probably enhances ischemia by vasoconstriction, mediated at least in part by increased ECE and ACE activity. In contrast, NEP activity may help to maintain cerebral perfusion, by reducing the accumulation of Aβ in cerebral blood vessels and lessening its toxicity to vascular smooth muscle cells. In assessing the role of Aβ-degrading proteases in the pathogenesis of AD and, particularly, their potential as therapeutic agents, it is important to bear in mind the multifunctional nature of these enzymes and to consider their effects on other substrates and pathways.
Highlights
The accumulation of Aβ within the brain is central to the pathogenesis of Alzheimer disease (AD)
We developed ELISA and immunocapture-based fluorogenic activity assays to measure the levels and/or specific enzyme activities of NEP, insulindegrading enzyme (IDE), endothelin-converting enzyme (ECE)-1, ECE-2, and angiotensin-converting enzyme (ACE) within biological tissue samples, including CSF, plasma, brain tissue homogenates and blood vessel preparations (Miners et al, 2008a,b), and used the concentration of neuronspecific enolase to adjust for neuronal content (Miners et al, 2009) in the case of NEP, IDE, ACE and ECE-2, and the concentration of factor VIII-related antigen to adjust for the endothelial cell content in the case of ECE-1 (Palmer et al, 2010)
In a large series of well-characterized human post-mortem brains, we found that NEP, IDE, ACE, and ECE-1 activities and ECE-2 levels were all higher in AD than in agematched controls (Miners et al, 2008c, 2009, 2010b; Palmer et al, 2009, 2010) and rose progressively with disease severity, as indicated by Braak tangle stage
Summary
The accumulation of Aβ within the brain is central to the pathogenesis of AD. The level of Aβ depends on its rate of production and on the rate of its removal via various clearance pathways including enzyme-mediated degradation. Findings from large post-mortem human brain studies and in vitro experiments have, revealed that the level and activity of many Aβ-degrading proteases are increased in post-mortem brain tissue and are upregulated by Aβ, suggesting that the increases are secondary to Aβ accumulation, possibly representing physiological responses to the rise in concentration of substrate.
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