title: Pyroglutamylated amyloid-β peptide reverses cross β-sheets by a prion-like mechanism.
abstract: The amyloid hypothesis causatively relates the fibrillar deposits of amyloid β peptide (Aβ) to Alzheimer's disease (AD). More recent data, however, identify the soluble oligomers as the major cytotoxic entities. Pyroglutamylated Aβ (pE-Aβ) is present in AD brains and exerts augmented neurotoxicity, which is believed to result from its higher β-sheet propensity and faster fibrillization. While this concept is based on a set of experimental results, others have reported similar β-sheet contents in unmodified and pyroglutamylated Aβ, and slower aggregation of pE-Aβ as compared to unmodified Aβ, leaving the issue unresolved. Here, we assess the structural differences between Aβ and pE-Aβ peptides that may underlie their distinct cytotoxicities. Transmission electron microscopy identifies a larger number of prefibrillar aggregates of pE-Aβ at early stages of aggregation and suggests that pE-Aβ affects the fibrillogenesis even at low molar fractions. Circular dichroism and FTIR data indicate that while the unmodified Aβ readily forms β-sheet fibrils in aqueous media, pE-Aβ displays increased α-helical and decreased β-sheet propensity. Moreover, isotope-edited FTIR spectroscopy shows that pE-Aβ reverses β-sheet formation and hence fibrillogenesis of the unmodified Aβ peptide via a prion-like mechanism. These data provide a novel structural mechanism for pE-Aβ hypertoxicity; pE-Aβ undergoes faster formation of prefibrillar aggregates due to its increased hydrophobicity, thus shifting the initial stages of fibrillogenesis toward smaller, hypertoxic oligomers of partial α-helical structure.
authors.affiliation: Biotechnology Graduate Program, University of Central Florida , 4000 Central Florida Boulevard, Orlando, Florida 32816, United States.
authors.forename: Jason O
authors.initials: JO
authors.lastname: Matos
authors.forename: Greg
authors.initials: G
authors.lastname: Goldblatt
authors.forename: Jaekyun
authors.initials: J
authors.lastname: Jeon
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Suren A
authors.initials: SA
authors.lastname: Tatulian
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011328:Prions / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D011328:Prions; D066329:Protein Aggregates; D018698:Glutamic Acid