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Neprilysin impedes islet amyloid formation by inhibition of fibril formation rather than peptide degradation

Zraika, Sakeneh, Aston-Mourney, Kathryn, Marek, Peter, Hull, Rebecca L., Green, Pattie S., Udayasankar, Jayalakshmi, Subramanian, Shoba L., Raleigh, Daniel P. and Kahn, Steven E. 2010, Neprilysin impedes islet amyloid formation by inhibition of fibril formation rather than peptide degradation, Journal of biological chemistry, vol. 285, no. 24, pp. 18177-18183, doi: 10.1074/jbc.M109.082032.

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Title Neprilysin impedes islet amyloid formation by inhibition of fibril formation rather than peptide degradation
Author(s) Zraika, Sakeneh
Aston-Mourney, KathrynORCID iD for Aston-Mourney, Kathryn orcid.org/0000-0003-1412-6715
Marek, Peter
Hull, Rebecca L.
Green, Pattie S.
Udayasankar, Jayalakshmi
Subramanian, Shoba L.
Raleigh, Daniel P.
Kahn, Steven E.
Journal name Journal of biological chemistry
Volume number 285
Issue number 24
Start page 18177
End page 18183
Total pages 7
Publisher American Society for Biochemistry and Molecular Biology
Place of publication Bethesda, Md.
Publication date 2010-06-11
ISSN 0021-9258
1083-351X
Keyword(s) amyloid
insulin secretion
pancreas
pancreatic islet
peptidases
islet amyloid
islet amyloid polypeptide
neprilysin
peptide degradation
type 2 diabetes
Summary Deposition of islet amyloid polypeptide (IAPP) as islet amyloid in type 2 diabetes contributes to loss of β-cell function and mass, yet the mechanism for its occurrence is unclear. Neprilysin is a metallopeptidase known to degrade amyloid in Alzheimer disease. We previously demonstrated neprilysin to be present in pancreatic islets and now sought to determine whether it plays a role in degrading islet amyloid. We used an in vitro model where cultured human IAPP (hIAPP) transgenic mouse islets develop amyloid and thereby have increased β-cell apoptosis. Islet neprilysin activity was inhibited or up-regulated using a specific inhibitor or adenovirus encoding neprilysin, respectively. Following neprilysin inhibition, islet amyloid deposition and β-cell apoptosis increased by 54 and 75%, respectively, whereas when neprilysin was up-regulated islet amyloid deposition and β-cell apoptosis both decreased by 79%. To determine if neprilysin modulated amyloid deposition by cleaving hIAPP, analysis of hIAPP incubated with neprilysin was performed by mass spectrometry, which failed to demonstrate neprilysin-induced cleavage. Rather, neprilysin may act by reducing hIAPP fibrillogenesis, which we showed to be the case by fluorescence-based thioflavin T binding studies and electron microscopy. In summary, neprilysin decreases islet amyloid deposition by inhibiting hIAPP fibril formation, rather than degrading hIAPP. These findings suggest that targeting the role of neprilysin in IAPP fibril assembly, in addition to IAPP cleavage by other peptidases, may provide a novel approach to reduce and/or prevent islet amyloid deposition in type 2 diabetes.
Language eng
DOI 10.1074/jbc.M109.082032
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047505

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.