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

  • Brain. 2019 May 1;142(5):1441-1457. doi: 10.1093/brain/awz066.
Gunnar Brinkmalm  1  2 ,  Wei Hong  3 ,  Zemin Wang  3 ,  Wen Liu  3 ,  Tiernan T O'Malley  3 ,  Xin Sun  3 ,  Matthew P Frosch  4 ,  Dennis J Selkoe  3 ,  Erik Portelius  1  2 ,  Henrik Zetterberg  1  2  5  6 ,  Kaj Blennow  1  2 ,  Dominic M Walsh  3
Affiliations
  • 1. Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, SE-431 80 Mölndal, Sweden.
  • 2. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, SE-431 80 Mölndal, Sweden.
  • 3. Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 4. Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
  • 5. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
  • 6. UK Dementia Research Institute at UCL, London, UK.
PMID: 31032851 DOI: 10.1093/brain/awz066
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.

Keywords
amyloid-β-protein; human neurons; long-term potentiation; mass spectrometry; video microscopy.
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