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Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain

Brinkmalm, G; Hong, W; Wang, Z; Liu, W; O'Malley, TT; Sun, X; Frosch, MP; ... Walsh, DM; + view all (2019) Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain. Brain , 142 (5) pp. 1441-1457. 10.1093/brain/awz066.

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Abstract

The primary structure of canonical amyloid-β-protein was elucidated more than 30 years ago, yet the forms of amyloid-β that play a role in Alzheimer’s disease pathogenesis remain poorly defined. Studies of Alzheimer’s disease brain extracts suggest that amyloid-β, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aβ), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aβ contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-β dimers may open a new phase of Alzheimer’s research and allow a better understanding of Alzheimer’s disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.

Type: Article
Title: Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain
Location: England
DOI: 10.1093/brain/awz066
Publisher version: https://doi.org/10.1093/brain/awz066
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Amyloid β-protein, long-term potentiation, human neurons, mass spectrometry, videomicroscopy.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10073499
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