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

摘要

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.