Contribution of advanced glycosylation to the amyloidogenicity of islet and amyloid polypeptide

Aphrodite Kapurniotu, Jürgen Bernhagen, Norma Greenfield, Yousef Al-Abed, Saul Teichberg, Rainer W. Frank, Wolfgang Voelter, Richard Bucala

Publikation: Beitrag in FachzeitschriftArtikelBegutachtung

95 Zitate (Scopus)

Abstract

The formation of amyloid within the islets of Langerhans is associated with the development of type II diabetes mellitus and occurs by the aggregation and insolubilization of islet amyloid polypeptide (IAPP). Recent in vitro studies suggest that amyloid formation follows a nucleation-dependent polymerization mechanism, i.e. aggregation is initiated by pre-formed aggregates or nucleation seeds. Modification of the Alzheimer's disease amyloid peptide by advanced glycosylation end products (AGEs), which form spontaneously by the non-enzymatic addition of glucose to protein amino groups, has been shown to enhance peptide aggregation in vitro. To explore the possibility that AGEs contribute to islet amyloid formation, we preparedAGE-modified IAPP (AGE-IAPP) in vitro and studied its properties by biochemical and biophysical techniques. AGE modification induced the formation of high-molecular-mass IAPP aggregates and amyloid formation was demonstrated by Congo red green-gold birefringence and by the presence of a characteristic fibrillar structure by electron microscopy. AGE-IAPP also showed an increase in cytotoxicity toward the astroglioma cell line HTB14. When added to soluble IAPP, AGE-IAPP seeds accelerated IAPP aggregation and abolished the nucleation period required for the polymerization of unseeded IAPP. Circular dichroism spectropolarimetry indicated that AGE-IAPP seeds may act as a template to stabilize the β-sheet conformation of IAPP, thereby promoting its aggregation. Our studies demonstrate that AGE modification of IAPP results in high-molecular mass, fibrillar amyloid structures that nucleate IAPP amyloid formation and suggest a model for intra-islet amyloid deposition that may occur by the progressive advanced glycosylation of IAPP in vivo.

OriginalspracheEnglisch
Seiten (von - bis)208-216
Seitenumfang9
FachzeitschriftEuropean Journal of Biochemistry
Jahrgang251
Ausgabenummer1-2
DOIs
PublikationsstatusVeröffentlicht - 15 Jan. 1998
Extern publiziertJa

Fingerprint

Untersuchen Sie die Forschungsthemen von „Contribution of advanced glycosylation to the amyloidogenicity of islet and amyloid polypeptide“. Zusammen bilden sie einen einzigartigen Fingerprint.

Dieses zitieren