title: Unmodified and pyroglutamylated amyloid β peptides form hypertoxic hetero-oligomers of unique secondary structure.
abstract: Amyloid β (Aβ) peptide plays a major role in Alzheimer's disease (AD) and occurs in multiple forms, including pyroglutamylated Aβ (AβpE). Identification and characterization of the most cytotoxic Aβ species is necessary for advancement in AD diagnostics and therapeutics. While in brain tissue multiple Aβ species act in combination, structure/toxicity studies and immunotherapy trials have been focused on individual forms of Aβ. As a result, the molecular composition and the structural features of "toxic Aβ oligomers" have remained unresolved. Here, we have used a novel approach, hydration from gas phase coupled with isotope-edited Fourier transform infrared (FTIR) spectroscopy, to identify the prefibrillar assemblies formed by Aβ and AβpE and to resolve the structures of both peptides in combination. The peptides form unusual β-sheet oligomers stabilized by intramolecular H-bonding as opposed to intermolecular H-bonding in the fibrils. Time-dependent morphological changes in peptide assemblies have been visualized by atomic force microscopy. Aβ/AβpE hetero-oligomers exert unsurpassed cytotoxic effect on PC12 cells as compared to oligomers of individual peptides or fibrils. These findings lead to a novel concept that Aβ/AβpE hetero-oligomers, not just Aβ or AβpE oligomers, constitute the main neurotoxic conformation. The hetero-oligomers thus present a new biomarker that may be targeted for development of more efficient diagnostic and immunotherapeutic strategies to combat AD.
authors.affiliation: Biomedical Sciences Graduate Program, University of Central Florida, Orlando, FL, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Goldblatt
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Cilenti
authors.affiliation: Biotechnology Graduate Program, University of Central Florida, Orlando, FL, USA.
authors.forename: Jason O
authors.initials: JO
authors.lastname: Matos
authors.affiliation: Nanotechnology Graduate Program, NanoScience Technology Center, University of Central Florida, Orlando, FL, USA.
authors.forename: Briana
authors.initials: B
authors.lastname: Lee
authors.affiliation: Nanotechnology Graduate Program, NanoScience Technology Center, University of Central Florida, Orlando, FL, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ciaffone
authors.affiliation: Physics Graduate Program, College of Sciences, University of Central Florida, Orlando, FL, USA.
authors.forename: Qing X
authors.initials: QX
authors.lastname: Wang
authors.affiliation: NanoScience Technology Center, University of Central Florida, Orlando, FL, USA.|Department of Physics, College of Sciences, University of Central Florida, Orlando, FL, USA.
authors.forename: Laurene
authors.initials: L
authors.lastname: Tetard
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Teter
authors.affiliation: Department of Physics, College of Sciences, University of Central Florida, Orlando, FL, USA.
authors.forename: Suren A
authors.initials: SA
authors.lastname: Tatulian
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002247:Carbon Isotopes; D002470:Cell Survival; D006801:Humans; D006860:Hydrogen Bonding; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D000072757:Protein Conformation, beta-Strand; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D016229:Amyloid beta-Peptides; D002247:Carbon Isotopes; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-
keywords: Alzheimer's disease; cytotoxicity; hydration from gas phase; isotope-edited infrared spectroscopy; α-β structural transition