Characterization of endopeptidase 3.4.24.11 (“enkephalinase”) activity in human plasma and cerebrospinal fluid

Reed

Journal of Biological Chemistry

2001

319

245

Deposition of ␤-amyloid (A␤) peptides in the brain is an early and invariant feature of all forms of Alzheimer's disease. As with any secreted protein, the extracellular concentration of A␤ is determined not only by its production but also by its catabolism. A major focus of Alzheimer's research has been the elucidation of the mechanisms responsible for the generation of A␤. Much less, however, is known about the mechanisms responsible for A␤ removal in the brain. In this report, we describe the identification of endothelin-converting enzyme-1 (ECE-1) as a novel A␤-degrading enzyme. We show that treatment of endogenous ECE-expressing cell lines with the metalloprotease inhibitor phosphoramidon causes a 2-3-fold elevation in extracellular A␤ concentration that appears to be due to inhibition of intracellular A␤ degradation. Furthermore, we show that overexpression of ECE-1 in Chinese hamster ovary cells, which lack endogenous ECE activity, reduces extracellular A␤ concentration by up to 90% and that this effect is completely reversed by treatment of the cells with phosphoramidon. Finally, we show that recombinant soluble ECE-1 is capable of hydrolyzing synthetic A␤40 and A␤42 in vitro at multiple sites.

Section: Resultsmentioning

confidence: 99%

Degradation of the Alzheimer's Amyloid β Peptide by Endothelin-converting Enzyme

Reed

Journal of Biological Chemistry

2001

319

245

“…The acute effects of NEP inhibitors on plasma ANF and cyclic GMP are similar both in sheep, which lack detectable NEP activity in plasma (unpublished observations from our laboratory), and in humans where plasma NEP activity is readily detectable. 29 Thus, it appears likely that local tissue NEP activity rather than circulating enzyme is the important regulator of the hormone's degradation.…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic and hormonal effects of neutral endopeptidase inhibitor SCH 39370 in sheep.

et al. 1991

Whole body clearance of atrial natriuretic factor is due to both receptor uptake and enzymatic degradation initiated by neutral endopeptidase 24.11. The effects of neutral endopeptidase inhibition have been studied in seven sodium-replete sheep using SCH 39370, a specific and potent inhibitor of neutral endopeptidase, in the presence or absence of exogenous hormone [rat ANF-(101-126), 2.4 pmol/kg/min for 2 hours]. SCH 39370 alone (2.5 mg/kg bolus) increased plasma atrial natriuretic factor and plasma cyclic GMP levels, lowered arterial pressure for periods beyond changes in plasma atrial natriuretic factor or cyclic GMP, and suppressed both plasma aldosterone and cortisol levels when compared with vehicle injections. The effects of SCH 39370 were similar to or exceeded those of atrial natriuretic factor infusions, which induced significantly greater increases in plasma atrial natriuretic factor (p-0.0l). Neither agent alone was natriuretic When SCH 39370 and atrial natriuretic factor were given together, plasma cyclic GMP but not atrial natriuretic factor levels were increased (/*=0.013) compared with atrial natriuretic factor infusion alone, and the half-life was prolonged (p=0.002) in the presence of SCH 39370. The hypotensive response was greater than that induced by atrial natriuretic factor alone (/?=0.03) but not different from SCH 39370 alone. Inhibitory effects of SCH 39370 on aldosterone levels were similar in the presence or absence of exogenous atrial natriuretic factor. Although not excluding actions of neutral endopeptidase inhibitors mediated by non-atrial natriuretic factor pathways, these results are consistent with a prolonged effect of neutral endopeptidase inhibition to increase tissue atrial natriuretic factor activity and provide further evidence of the importance of neutral endopeptidase in atrial natriuretic factor physiology. (Hypertension 1991;17:643-651) A trial natriuretic factor (ANF), a circulating peptide with potent effects on renal, cardiovascular, and hormonal systems, appears to be an important new hormonal regulator of body fluid and blood pressure. Many of the actions of the hormone have therapeutic potential-particularly when normal pressure-volume relations are disrupted, as in hypertension, heart failure, and renal failure. However, techniques to increase blood or tissue hormone concentrations are made difficult by its polypeptide nature and rapid clearance from the circulation.

International Journal of Alzheimer's Disease

“…It is a preferentially membrane-bound, presynaptically located protein with an extracellular catalytic site which can degrade Abeta [90, 91]. A soluble form of NEP is detectable in body fluids such as blood and CSF, emanating from a slow release from the membranes [92]. Most interestingly, reduced CSF NEP activity levels have been shown to occur in early AD [93, 94].…”

Section: Abeta Clearance: Lessons From Alzheimer's Disease Researchmentioning

confidence: 99%

Protein Clearance Mechanisms of Alpha-Synuclein and Amyloid-Beta in Lewy Body Disorders

Deleidi

Maetzler

2012

Protein clearance is critical for the maintenance of the integrity of neuronal cells, and there is accumulating evidence that in most—if not all—neurodegenerative disorders, impaired protein clearance fundamentally contributes to functional and structural alterations eventually leading to clinical symptoms. Dysfunction of protein clearance leads to intra- and extraneuronal accumulation of misfolded proteins and aggregates. The pathological hallmark of Lewy body disorders (LBDs) is the abnormal accumulation of misfolded proteins such as alpha-synuclein (Asyn) and amyloid-beta (Abeta) in a specific subset of neurons, which in turn has been related to deficits in protein clearance. In this paper we will highlight common intraneuronal (including autophagy and unfolded protein stress response) and extraneuronal (including interaction of neurons with astrocytes and microglia, phagocytic clearance, autoimmunity, cerebrospinal fluid transport, and transport across the blood-brain barrier) protein clearance mechanisms, which may be altered across the spectrum of LBDs. A better understanding of the pathways underlying protein clearance—in particular of Asyn and Abeta—in LBDs may result in the identification of novel biomarkers for disease onset and progression and of new therapeutic targets.