Structural conversion of neurotoxic amyloid-β(1–42) oligomers to fibrils

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Abstract

The Aβ42 peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low temperature and low salt can stabilize disc-shaped oligomers (pentamers) that are significantly more toxic to murine cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the β-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C-terminus is protected from solvent exchange and which have a turn conformation placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Aβ42 oligomers to fibrils involves the association of these loosely aggregated strands into β-sheets whose individual β-strands polymerize in a parallel, in-register orientation and are staggered at an inter-monomer contact between Gln15 and Gly37.

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Most cited references 30

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A specific amyloid-beta protein assembly in the brain impairs memory.

Sylvain Lesne, Ming Teng Koh, Linda Kotilinek … (2006)

Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice ( 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

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Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.

C A McLean, R A Cherny, F W Fraser … (1999)

Genetic evidence strongly supports the view that Abeta amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentation, and form of Abeta and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble Abeta were determined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble Abeta is increased threefold in Alzheimer's disease and correlates highly with markers of disease severity. In contrast, the level of insoluble Abeta (also a measure of total amyloid load) is found only to discriminate Alzheimer's disease from controls, and does not correlate with disease severity or numbers of amyloid plaques. These findings support the concept of several interacting pools of Abeta, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. The latter may exist in both intracellular and extracellular compartments, and contain the basic forms of Abeta that cause neurodegeneration. Reducing the levels of these soluble Abeta species by threefold to levels found in normal controls might prove to be a goal of future therapeutic intervention.

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Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.

L Lue, Y M Kuo, A Roher … (1999)

We have characterized amyloid beta peptide (Abeta) concentration, Abeta deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Abeta deposition, Abeta-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Abeta, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Abeta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Abeta40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Abeta42. Abeta40 is known to be elevated in cerebrovascular amyloid deposits, and Abeta40 (but not Abeta42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Abeta, particularly soluble Abeta40. Previous experiments attempting to relate Abeta deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101186374

Journal ID (pubmed-jr-id): 31761

Journal ID (nlm-ta): Nat Struct Mol Biol

Title: Nature structural & molecular biology

ISSN (Print): 1545-9993

ISSN (Electronic): 1545-9985

Publication date Nihms-submitted: 23 July 2010

Publication date (Electronic): 11 April 2010

Publication date (Print): May 2010

Publication date PMC-release: 1 November 2010

Volume: 17

Issue: 5

Pages: 561-567

Affiliations

[1 ]Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794-5215

[2 ]Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York 11794-5215

[3 ]Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan

[4 ]Department of Physics and Astronomy, Stony Brook University, Stony Brook, New York 11794-5215

[5 ]Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520

Author notes

Correspondence should be addressed to S.O.S. ( steven.o.smith@ 123456sunysb.edu )

Article

Manuscript ID: nihpa223271

DOI: 10.1038/nsmb.1799

PMC ID: 2922021

PubMed ID: 20383142

SO-VID: 87fbef6d-0019-4080-b7a6-76906446e151

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