title: Amyloid β-induced astrogliosis is mediated by β1-integrin via NADPH oxidase 2 in Alzheimer's disease.
abstract: 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-β modulates β1-integrin activity and triggers NADPH oxidase (NOX)-dependent astrogliosis in vitro and in vivo. Amyloid-β oligomers activate a PI3K/classical PKC/Rac1/NOX pathway which is initiated by β1-integrin in cultured astrocytes. This mechanism promotes β1-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 β1-integrin in reactive astrocytes which correlates with the amyloid β-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 β1-integrin in that cortical region and specifically in reactive astrocytes, which was most prominent at advanced AD stages. Importantly, protein levels of NOX2 and β1-integrin were significantly associated with increased amyloid-β load in human samples. These data strongly suggest that astrogliosis in AD is caused by direct interaction of amyloid β oligomers with β1-integrin which in turn leads to enhancing β1-integrin and NOX2 activity via NOX-dependent mechanisms. These observations may be relevant to AD pathophysiology.
authors.affiliation: Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain.|Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.|Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain.
authors.forename: Ane
authors.initials: A
authors.lastname: Wyssenbach
authors.affiliation: Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain.|Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.|Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Quintela
authors.affiliation: Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain.|Departamento de Genética, Antropología Física y Fisiología Animal, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Llavero
authors.affiliation: Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain.|Departamento de Genética, Antropología Física y Fisiología Animal, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain.|IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013, Bilbao, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Zugaza
authors.affiliation: Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain.|Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.|Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.affiliation: Departamento de Neurociencias, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain.|Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Leioa, Spain.|Achucarro Basque Center for Neuroscience, 48940, Leioa, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Alberdi
keywords: Alzheimer′s disease; NOX2; amyloid-β; astroglia; β1-integrin