Unmodified And Pyroglutamylated Amyloid Β Peptides Form Hypertoxic Hetero-Oligomers Of Unique Secondary Structure

Keywords

Alzheimer's disease; cytotoxicity; hydration from gas phase; isotope-edited infrared spectroscopy; α-β structural transition

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.

Publication Date

5-1-2017

Publication Title

FEBS Journal

Volume

284

Issue

9

Number of Pages

1355-1369

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1111/febs.14058

Socpus ID

85017665894 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85017665894

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