Biochemical Identification of the Neutral Endopeptidase Family Member Responsible for the Catabolism of Amyloid   Peptide in the Brain

Takaki, Yoshie; Iwata, Nobuhisa; Tsubuki, Satoshi; Taniguchi, Shoichi; Toyoshima, Satoshi; Lu, Bao Yuan; Gerard, Norma P.; Gérard, Craig; Lee, Hahn-Jun; Shirotani, Keiro; Saido, Takaomi C.

doi:10.1093/oxfordjournals.jbchem.a022839

Cited by 94 publications

(67 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Neprilysin is supposed to be involved in the catabolism of various neuropeptides, such as enkephalin, substance P, somatostatin, and kinins (Turner, 1998), and is currently regarded as a major A␤-degrading enzyme Takaki et al, 2000;Shirotani et al, 2001;Carson and Turner, 2002;Saido, 2003;Saido and Nakahara, 2003;Saito et al, 2003). In the present study, we expressed neprilysin in the hippocampal formation of mice using rAAV-based vectors and successfully reduced A␤ levels in that region; neprilysin gene transfer abolished the increase in A␤ levels in neprilysin-deficient mice, reduced A␤ in young mutant APP transgenic mice and was also effective in the deceleration of A␤ deposition in the brain of aged mutant APP transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid-β Peptide in Mouse Brain

Iwata

Mizukami²,

Shirotani³

et al. 2004

J. Neurosci.

Self Cite

230

182

View full text Add to dashboard Cite

A local increase in amyloid-␤ peptide (A␤) is closely associated with synaptic dysfunction in the brain in Alzheimer's disease. Here, we report on the catabolic mechanism of A␤ at the presynaptic sites. Neprilysin, an A␤-degrading enzyme, expressed by recombinant adeno-associated viral vector-mediated gene transfer, was axonally transported to presynaptic sites through afferent projections of neuronal circuits. This gene transfer abolished the increase in A␤ levels in the hippocampal formations of neprilysin-deficient mice and also reduced the increase in young mutant amyloid precursor protein transgenic mice. In the latter case, A␤ levels in the hippocampal formation contralateral to the vector-injected side were also significantly reduced as a result of transport of neprilysin from the ipsilateral side, and in both sides soluble A␤ was degraded more efficiently than insoluble A␤. Furthermore, amyloid deposition in aged mutant amyloid precursor protein transgenic mice was remarkably decelerated. Thus, presynaptic neprilysin has been demonstrated to degrade A␤ efficiently and to retard development of amyloid pathology.

show abstract

Section: Discussionmentioning

confidence: 99%

Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid-β Peptide in Mouse Brain

Iwata

Mizukami²,

Shirotani³

et al. 2004

J. Neurosci.

Self Cite

230

182

View full text Add to dashboard Cite

show abstract

“…Digestion of A␤40 in this experiment resulted in the formation of four major product peaks, similar to that which was observed with the 3 H-labeled peptide. The major peaks were further analyzed by mass spectrometry and NH 2 -terminal sequencing, leading to the identification of three NH 2 -terminal fragments: A␤-(1-16), A␤-(1-17), and A␤- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Only one C-terminal fragment was observed, which corresponds to A␤- (20 -40) (Fig.…”

Section: Fig 4 Removal Of Exogenous Synthetic A␤ By Ece-overexpressmentioning

confidence: 99%

“…Recent reports suggest a role for both insulin-degrading enzyme and neprilysin (NEP) in the degradation of extracellular A␤ (3)(4)(5)(6)(7)(8)(9)(10). Matrix metalloproteinase-9, EC 3.4.24.15, and ␣ 2 -macroglobulin complexes have also been reported to play a role in A␤ degradation (11)(12)(13).…”

mentioning

confidence: 99%

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

Eckman

Reed

Eckman

2001

Journal of Biological Chemistry

321

245

View full text Add to dashboard Cite

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.

show abstract

“…Several proteases have been shown to be capable of cleaving Ab peptide. There are number of candidate proteases, including trypsin and a-chymotrypsin [27], insulin degrading enzyme [28][29][30], endothelin-converting enzyme [31], carboxypeptidase B [32], angiotensin-converting enzyme [33], plasmin [34,35], neprilysin [36] and cathepsin D [20,21]. However, the enzyme definitively responsible for the physiological degradation of Ab peptide is thus far unclear.…”

Section: Discussionmentioning

confidence: 99%

Aluminum inhibits proteolytic degradation of amyloid β peptide by cathepsin D: A potential link between aluminum accumulation and neuritic plaque deposition

et al. 2006

View full text Add to dashboard Cite

Neuritic plaques are the key pathological feature of Alzheimer's disease, and amyloid b (Ab) peptides are major component of these plaques. In this study, we demonstrated the influence of aluminum (Al) on the Ab peptide degradation by cathepsin D. Al did not directly affect the cathepsin D activity using small synthetic substrate. However, when Ab peptides were used as substrate, the apparent inhibitory effect of Al on cathepsin D activity was observed. This inhibitory effect disappeared by treatment of desferrioxamine. These results indicate that Al has the potential to interact and disrupt Ab peptide catabolism via the inhibition of proteolytic degradation.

show abstract

Biochemical Identification of the Neutral Endopeptidase Family Member Responsible for the Catabolism of Amyloid Peptide in the Brain

Cited by 94 publications

References 0 publications

Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid-β Peptide in Mouse Brain

Presynaptic Localization of Neprilysin Contributes to Efficient Clearance of Amyloid-β Peptide in Mouse Brain

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

Aluminum inhibits proteolytic degradation of amyloid β peptide by cathepsin D: A potential link between aluminum accumulation and neuritic plaque deposition

Contact Info

Product

Resources

About