Title: Pyroglutamylated Amyloid-Beta Peptide Reverses Cross Beta-Sheets by a Prion-Like Mechanism
Abstract: The amyloid hypothesis causatively relates the extracellular fibrillar deposits of amyloid beta peptide (Abeta) to the Alzheimer's disease (AD). More recent data, however, identify the intracellular oligomers as the major cytotoxic entities. Pyroglutamylated Abeta (pE-Abeta) is present in AD brains and exerts augmented neurotoxicity by an unknown mechanism. The hypertoxicity of pE-Abeta is believed to result from its higher beta-sheet propensity and faster conversion into fibrils. While this concept is based on a set of experimental results, others have reported similar beta-sheet contents in unmodified and pE-Abeta, and even slower aggregation of pE-Abeta as compared to unmodified Abeta, leaving the issue unresolved. Here, we show by a variety of biophysical approaches, including isotope-edited FTIR spectroscopy, that pE-Abeta not only has a higher alpha-helix and lower beta-sheet propensity itself but also reverses beta-sheet formation and hence fibrillogenesis of the unmodified Abeta peptide via a prion-like mechanism.These data provide a structural mechanism for pE-Abeta hypertoxicity; pE-Abeta undergoes faster nucleation due to its increased hydrophobicity, thus promoting formation of hypertoxic oligomers of partial alpha-helical structure.