Abstract
Increasing evidence highlights the central role of neurotoxic oligomers of the 42-residue-long β-amyloid (Aβ42) in Alzheimer's disease (AD). However, very limited information is available on the structural transition from oligomer to fibril, particularly for pathologically relevant amyloids. To the best of our knowledge, we present here the first site-specific structural characterization of Aβ42 misfolding, from toxic oligomeric assembly yielding a similar conformation to an AD-associated Aβ42 oligomer, into a fibril. Transmission EM (TEM) analysis revealed that a spherical amyloid assembly (SPA) of Aβ42 with a 15.6 ± 2.1-nm diameter forms in a ∼30-μm Aβ42 solution after a ∼10-h incubation at 4 °C, followed by a slow conversion into fibril at ∼180 h. Immunological analysis suggested that the SPA has a surface structure similar to that of amylospheroid (ASPD), a patient-derived toxic Aβ oligomer, which had a diameter of 10-15 nm in negative-stain TEM. Solid-state NMR analyses indicated that the SPA structure involves a β-loop-β motif, which significantly differed from the triple-β motif observed for the Aβ42 fibril. The comparison of the 13C chemical shifts of SPA with those of the fibril prepared in the above conditions and interstrand distance measurements suggested a large conformational change involving rearrangements of intermolecular β-sheet into in-register parallel β-sheet during the misfolding. A comparison of the SPA and ASPD 13C chemical shifts indicated that SPA is structurally similar to the ASPD relevant to AD. These observations provide insights into the architecture and key structural transitions of amyloid oligomers relevant for AD pathology.
Highlights
Increasing evidence highlights the central role of neurotoxic oligomers of the 42-residue-long -amyloid (A42) in Alzheimer’s disease (AD)
The atomic structures of amyloid intermediates pathogenically relevant for AD have attracted considerable attention, as the structural features of the A oligomers would provide important understanding of the amyloid formation in AD, which may lead to plausible therapeutic interference against A oligomers or fibrils
These results indicate that A42 was misfolded into spherical amyloid assembly (SPA) at an early stage of the incubation (7–12 h) and that SPA remained stable at t ϳ50 h
Summary
Increasing evidence highlights the central role of neurotoxic oligomers of the 42-residue-long -amyloid (A42) in Alzheimer’s disease (AD). Immunological analysis suggested that the SPA has a surface structure similar to that of amylospheroid (ASPD), a patient-derived toxic A oligomer, which had a diameter of 10 –15 nm in negative-stain TEM. Recent studies suggested that some diffusible A assemblies exhibit much higher cytotoxicity than A fibrils [2,3,4,5,6,7,8,9,10,11] These studies provided support for a revised amyloid-cascade hypothesis, asserting that neural cell death in early AD may be caused by diffusible aggregates of A rather than fibrils [10, 12, 13]. Almost no structural information has been reported for other pathologically relevant A oligomers
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