A calcium-sensitive antibody isolates soluble amyloid-β aggregates and fibrils from Alzheimer's disease brain

Brain. 2022 Jul 29;145(7):2528-2540. doi: 10.1093/brain/awac023.


Aqueously soluble oligomers of amyloid-β peptide may be the principal neurotoxic forms of amyloid-β in Alzheimer's disease, initiating downstream events that include tau hyperphosphorylation, neuritic/synaptic injury, microgliosis and neuron loss. Synthetic oligomeric amyloid-β has been studied extensively, but little is known about the biochemistry of natural oligomeric amyloid-β in human brain, even though it is more potent than simple synthetic peptides and comprises truncated and modified amyloid-β monomers. We hypothesized that monoclonal antibodies specific to neurotoxic oligomeric amyloid-β could be used to isolate it for further study. Here we report a unique human monoclonal antibody (B24) raised against synthetic oligomeric amyloid-β that potently prevents Alzheimer's disease brain oligomeric amyloid-β-induced impairment of hippocampal long-term potentiation. B24 binds natural and synthetic oligomeric amyloid-β and a subset of amyloid plaques, but only in the presence of Ca2+. The amyloid-β N terminus is required for B24 binding. Hydroxyapatite chromatography revealed that natural oligomeric amyloid-β is highly avid for Ca2+. We took advantage of the reversible Ca2+-dependence of B24 binding to perform non-denaturing immunoaffinity isolation of oligomeric amyloid-β from Alzheimer's disease brain-soluble extracts. Unexpectedly, the immunopurified material contained amyloid fibrils visualized by electron microscopy and amenable to further structural characterization. B24-purified human oligomeric amyloid-β inhibited mouse hippocampal long-term potentiation. These findings identify a calcium-dependent method for purifying bioactive brain oligomeric amyloid-β, at least some of which appears fibrillar.

Keywords: Alzheimer; amyloid; antibody; calcium; synaptotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antibodies / metabolism
  • Brain / metabolism
  • Calcium / metabolism
  • Humans
  • Mice
  • Plaque, Amyloid / metabolism


  • Amyloid beta-Peptides
  • Antibodies
  • Calcium