Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia.

MORELLI, L., LLOVERA R.E., ALONSO, L.G., FRANGIONE, B., PRAT GAY, G. DE, GHISO, J. AND CASTAÑO, E.M.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Año: 2005 vol. 332 p. 806 - 814

0006-291X

Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia Laura Morelli a, Ramiro E. Llovera a, Leonardo G. Alonso a, Blas Frangione b,c, Gonzalo de Prat-Gay a, Jorge Ghiso b,c, Eduardo M. Castaño a,* a Fundación Instituto Leloir, Instituto de Investigaciones Bioqu?´ micas de Buenos Aires, (CONICET), Patricias Argentinas 435, Buenos Aires 1405, Argentina b Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA c Department of Psychiatry, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA Received 4 May 2005 Available online 13 May 2005 Abstract Familial British dementia (FBD) and familial Danish dementia (FDD) are autosomal dominant disorders characterized by cerebrovascular and parenchymal amyloid deposition and neurofibrillary degeneration. In both conditions, the genetic defects cause the loss of the normal stop codon in the precursor BRI, generating novel 34-residue peptides named ABri and ADan in FBD and FDD, respectively. ABri and ADan show a strong tendency to aggregate into non-fibrillar and fibrillar structures at neutral pH and this property seems to be directly related to neurotoxicity. Here we report that a recombinant insulin-degrading enzyme (rIDE) was capable of degrading monomeric ABri and ADan in vitro more efficiently than oligomeric species. These peptides showed high b-structure content and were more resistant to proteolysis as compared to the BRI wild-type product of 23 amino acids. Specific sites of cleavage within the C-terminal pathogenic extensions raise the possibility that proteolysis of monomeric soluble precursors by IDE may delay ABri and ADan aggregation in vivo. Keywords: Amyloid; Degradation; Hereditary dementia; Insulin-degrading enzyme; Neurodegeneration; Cerebrovascular amyloidoses