Date Published: October 05, 2016
Publisher: John Wiley and Sons Inc.
Author(s): Ane Wyssenbach, Tania Quintela, Francisco Llavero, Jose L. Zugaza, Carlos Matute, Elena Alberdi.
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.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive function. The mechanisms underlying AD include an interplay between direct neurotoxicity, cerebrovascular pathology, inflammation, and cortical network dysfunction (Iadecola, 2004; Haass & Selkoe, 2007; Palop & Mucke, 2010). Whereas neuronal death has taken center stage in AD pathology, the putative contribution of glia to this disease has not been closely examined.
Astrogliosis is a neuropathologic hallmark in AD whose severity strongly correlates with the density of reactive astrocytes and the robust increase in GFAP in both brain and CSF (Muramori et al., 1998; Fukuyama et al., 2001). In the present study, we unveiled a new mechanistic pathway that drives astrogliosis in AD‐like pathology. Thus, our data indicate that amyloid‐β oligomers modulate integrin receptor activity in astrocytes which ultimately results in GFAP upregulation through NADPH oxidase‐mediated redox signaling (Fig S1, Supporting information). This idea is further supported by the presence of elevated expression of β1‐integrin and NOX2 which correlate with amyloid β load in vivo models of AD and in the disease proper.
This study was supported by CIBERNED and by grants from Ministerio de Economía y Competitividad (SAF2013‐45084‐R), Gobierno Vasco, Ikerbasque, and Universidad del País Vasco. A.W. held a fellowship from UPV/EHU and T.Q. from Gobierno Vasco.
AW, CM, EA wrote the manuscript; all others received and approved the manuscript. AW, TQ, FL, JLZ, CM, and EA performed experiments. AW, CM, and EA analyzed data. CM and EA supervised the project.