Proteolytically Inactive Insulin-Degrading Enzyme Inhibits Amyloid Formation Yielding Non-Neurotoxic Ab Peptide Aggregates

DE TULLIO MB; CASTELLETTO V; HAMLEY IW; MARTINO ADAMI P; MORELLI L; CASTAÑO EM

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2013 vol. 8 p. 1 - 13

1932-6203

Insulin-degrading enzyme (IDE) is a neutral Zn2+ peptidase that degrades short peptides based on substrate conformation,size and charge. Some of these substrates, including amyloid b (Ab) are capable of self-assembling into cytotoxic oligomers.Based on IDE recognition mechanism and our previous report of the formation of a stable complex between IDE and intactAb in vitro and in vivo, we analyzed the possibility of a chaperone-like function of IDE. A proteolytically inactive recombinantIDE with Glu111 replaced by Gln (IDEQ) was used. IDEQ blocked the amyloidogenic pathway of Ab yielding non-fibrillarstructures as assessed by electron microscopy. Measurements of the kinetics of Ab aggregation by light scattering showedthat 1) IDEQ effect was promoted by ATP independent of its hydrolysis, 2) end products of Ab-IDEQ co-incubation wereincapable of ‘‘seeding’’ the assembly of monomeric Ab and 3) IDEQ was ineffective in reversing Ab aggregation. Moreover,Ab aggregates formed in the presence of IDEQ were non-neurotoxic. IDEQ had no conformational effects upon insulin (anon-amyloidogenic protein under physiological conditions) and did not disturb insulin receptor activation in cultured cells.Our results suggest that IDE has a chaperone-like activity upon amyloid-forming peptides. It remains to be exploredwhether other highly conserved metallopeptidases have a dual protease-chaperone function to prevent the formation oftoxic peptide oligomers from bacteria to mammals.