Neurotoxicity and memory deficits induced by soluble low-molecular-weight amyloid-β1-42 oligomers are revealed in vivo by using a novel animal model

J Neurosci. 2012 Jun 6;32(23):7852-61. doi: 10.1523/JNEUROSCI.5901-11.2012.


Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-β (Aβ) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with Aβ lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble Aβ(1-42) oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small Aβ(1-42) species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic Aβ(1-42) species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble Aβ(1-42) oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Avoidance Learning
  • Blotting, Western
  • Cell Survival / drug effects
  • Female
  • Formates / pharmacology
  • Hippocampus
  • Immunohistochemistry
  • Injections
  • Isomerism
  • Maze Learning / physiology
  • Memory Disorders / chemically induced*
  • Memory Disorders / pathology
  • Memory Disorders / psychology
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Molecular Weight
  • Neurons / pathology
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / psychology*
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / chemistry
  • Peptide Fragments / toxicity*
  • Phosphorylation
  • Prealbumin / pharmacology
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Formates
  • Peptide Fragments
  • Prealbumin
  • amyloid beta-protein (1-42)
  • tau Proteins
  • formic acid