Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer's disease

Nat Commun. 2014 Mar 6:5:3443. doi: 10.1038/ncomms4443.

Abstract

Reelin is an extracellular matrix protein that is crucial for neural development and adult brain plasticity. While the Reelin signalling cascade has been reported to be associated with Alzheimer's disease (AD), the role of Reelin in this pathology is not understood. Here we use an in vitro approach to show that Reelin interacts with amyloid-β (Aβ42) soluble species, delays Aβ42 fibril formation and is recruited into amyloid fibrils. Furthermore, Reelin protects against both the neuronal death and dendritic spine loss induced by Aβ42 oligomers. In mice carrying the APP(Swe/Ind) mutation (J20 mice), Reelin overexpression delays amyloid plaque formation and rescues the recognition memory deficits. Our results indicate that by interacting with Aβ42 soluble species, delaying Aβ plaque formation, protecting against neuronal death and dendritic spine loss and preventing AD cognitive deficits, the Reelin pathway deserves consideration as a therapeutic target for the treatment of AD pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Amyloid / metabolism*
  • Amyloid / ultrastructure
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Behavior, Animal / physiology
  • Blotting, Western
  • Brain / metabolism
  • Brain / pathology
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cells, Cultured
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism
  • Cognition Disorders / physiopathology
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / metabolism
  • Protein Binding
  • Reelin Protein
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*

Substances

  • Amyloid
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Cell Adhesion Molecules, Neuronal
  • Extracellular Matrix Proteins
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Reelin Protein
  • amyloid beta-protein (1-42)
  • RELN protein, human
  • Reln protein, mouse
  • Serine Endopeptidases