Amyloid β-induced astrogliosis is mediated by β1-integrin via NADPH oxidase 2 in Alzheimer's disease

Astrogliosis is a hallmark of Alzheimer's disease (AD) and may constitute a primary pathogenic component of that disorder. Elucidation of signaling cascades inducing astrogliosis should help characterizing the function of astrocytes and identifying novel molecular targets to modulate AD progression. Here, we describe a novel mechanism by which soluble amyloid-beta modulates 1-integrin activity and triggers NADPH oxidase (NOX)-dependent astrogliosis in vitro and in vivo. Amyloid-beta oligomers activate a PI3K/classical PKC/Rac1/NOX pathway which is initiated by beta 1-integrin in cultured astrocytes. This mechanism promotes beta 1-integrin maturation, upregulation of NOX2 and of the glial fibrillary acidic protein (GFAP) in astrocytes in vitro and in hippocampal astrocytes in vivo. Notably, immunochemical analysis of the hippocampi of a triple-transgenic AD mouse model shows increased levels of GFAP, NOX2, and beta 1-integrin in reactive astrocytes which correlates with the amyloid beta-oligomer load. Finally, analysis of these proteins in postmortem frontal cortex from different stages of AD (II to V/VI) and matched controls confirmed elevated expression of NOX2 and beta 1-integrin in that cortical region and specifically in reactive astrocytes, which was most prominent at advanced AD stages. Importantly, protein levels of NOX2 and beta 1-integrin were significantly associated with increased amyloid-beta load in human samples. These data strongly suggest that astrogliosis in AD is caused by direct interaction of amyloid beta oligomers with beta 1-integrin which in turn leads to enhancing beta 1-integrin and NOX2 activity via NOX-dependent mechanisms. These observations may be relevant to AD pathophysiology.