2. Academic Validation
  3. Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain

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

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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