Tetracycline affects abnormal properties of synthetic PrP peptides and PrPSc in vitro

Prion diseases are characterized by the accumulation of altered forms of th e prion protein (termed PrPSc) in the brain. Unlike the normal protein, PrP Sc isoforms have a high content of beta-sheet secondary structure, are prot ease-resistant, and form insoluble aggregates and amyloid fibrils. Evidence indicates that they are responsible for neuropathological changes (i.e. ne rve cell degeneration and glial cell activation) and transmissibility of th e disease process. Here, we show that the antibiotic tetracycline: (i) bind s to amyloid fibrils generated by synthetic peptides corresponding to resid ues 106-126 and 82-146 of human PrP; (ii) hinders assembly of these peptide s into amyloid fibrils; (iii) reverts the protease resistance of PrP peptid e aggregates and PrPSc extracted from brain tissue of patients with Creutzf eldt-Jakob disease; (iv) prevents neuronal death and astrocyte proliferatio n induced by PrP peptides in vitro. NMR spectroscopy revealed several throu gh-space interactions between aromatic protons of tetracycline and side-cha in protons of Ala(117-119), Val(121-122) and Leu(125) of PrP 106-126. These properties make tetracycline a prototype of compounds with the potential o f inactivating the pathogenic forms of PrP. (C) 2000 Academic Press.