Recombinant Integrin β1 Signal Peptide Blocks Gliosis Induced by Aβ Oligomers

Glial cells participate actively in the early cognitive decline in Alzheimer's disease (AD) pathology. In fact, recent studies have found molecular and functional abnormalities in astrocytes and microglia in both animal models and brains of patients suffering from this pathology. In this regard, reactive gliosis intimately associated with amyloid plaques has become a pathological hallmark of AD. A recent study from our laboratory reports that astrocyte reactivity is caused by a direct interaction between amyloid beta (A beta) oligomers and integrin beta 1. Here, we have generated four recombinant peptides including the extracellular domain of integrin beta 1, and evaluated their capacity both to bind in vitro to A beta oligomers and to prevent in vivo A beta oligomer-induced gliosis and endoplasmic reticulum stress. We have identified the minimal region of integrin beta 1 that binds to A beta oligomers. This region is called signal peptide and corresponds to the first 20 amino acids of the integrin beta 1 N-terminal domain. This recombinant integrin beta 1 signal peptide prevented A beta oligomer-induced ROS generation in primary astrocyte cultures. Furthermore, we carried out intrahippocampal injection in adult mice of recombinant integrin beta 1 signal peptide combined with or without A beta oligomers and we evaluated by immunohistochemistry both astrogliosis and microgliosis as well as endoplasmic reticulum stress. The results show that recombinant integrin beta 1 signal peptide precluded both astrogliosis and microgliosis and endoplasmic reticulum stress mediated by A beta oligomers in vivo. We have developed a molecular tool that blocks the activation of the molecular cascade that mediates gliosis via A beta oligomer/integrin beta 1 signaling.

Automated summary

Glial cells play an important role in Alzheimer's disease and their activation is caused by the interaction between A beta oligomers and integrin beta 1. The recombinant integrin beta 1 signal peptide can block the generation of ROS and endoplasmic reticulum stress induced by A beta oligomers, as well as prevent gliosis and endoplasmic reticulum stress in vivo.