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

Abstract

SummaryAstrogliosis is a hallmark of Alzheimer 0 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-b modulates b1-integrin activity and triggers NADPH oxidase (NOX)-dependent astrogliosis in vitro and in vivo. Amyloid-b oligomers activate a PI3K/classical PKC/Rac1/NOX pathway which is initiated by b1-integrin in cultured astrocytes. This mechanism promotes b1-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 b1-integrin in reactive astrocytes which correlates with the amyloid boligomer 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 b1-integrin in that cortical region and specifically in reactive astrocytes, which was most prominent at advanced AD stages. Importantly, protein levels of NOX2 and b1-integrin were significantly associated with increased amyloid-b load in human samples. These data strongly suggest that astrogliosis in AD is caused by direct interaction of amyloid b oligomers with b1-integrin which in turn leads to enhancing b1-integrin and NOX2 activity via NOX-dependent mechanisms. These observations may be relevant to AD pathophysiology.

Early Effects of Aβ Oligomers on Dendritic Spine Dynamics and Arborization in Hippocampal Neurons

“…A large number of possible Aβ receptors have been suggested (Jarosz-Griffiths et al, 2016). Interaction between integrins, a large family of extracellular matrix receptors, and Aβ peptides promote neurotoxicity and inhibition of LTP (Wang et al, 2008), mitochondrial and synaptic dysfunction (Woo et al, 2015), gliosis (Wyssenbach et al, 2016) and oligodendrocyte differentiation Quintela-López et al, 2019). In the developing and adult brain, many integrins are present at high levels at synapses (for review, Park and Goda, 2016).…”

“…Selective loss of this receptor in excitatory neurons leads to reductions in the size and complexity of hippocampal dendritic arbors, hippocampal synapse loss and impaired hippocampusdependent learning (Warren et al, 2012). Additionally, integrin β1 mRNA and protein levels are upregulated by Aβ oligomers in astrocytes and oligodendrocytes suggesting that Aβ peptides might change the dynamic nature of integrin expression and function throughout AD (Wyssenbach et al, 2016;Quintela-López et al, 2019). Notably, we observed that spine density and specifically the fraction of stubby spines returned to control levels when integrin β1 was reduced with blocking antibodies.…”

“…Aβ oligomers require the activity of protein kinase CaMKII and receptor integrin β1 to induce synaptotoxicity and astrogliosis, respectively (Wyssenbach et al, 2016;Opazo et al, 2018). To determine whether CaMKII and integrin β1 were also involved in acute Aβ-mediated spine modifications, EGFP-expressing slices were pretreated with the CaMKII inhibitor AIP, the integrin β1 blocker antibody CD29, and the isotype control antibody IgM (Yokosaki et al, 1994;Ishida et al, 1995).…”

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

“…(23,35,36,53,54). The close relationship between the levels of Aβ and NOX2 activity has also been well documented in multiple studies (22,38,(55)(56)(57)(58)(59).…”

MicroRNA-211/BDNF axis regulates LPS-induced proliferation of normal human astrocyte through PI3K/AKT pathway

“…In the meantime, SCI triggers astrocytes to become reactive and initiate astrogliosis [ 31 , 32 ]. Reactive astrogliosis is characterized by the proliferation and hypertrophy of astrocytes, which eventually leads to scar formation via the effects of neurotrophic factors such as BDNF [ 33 ], or activation of signaling pathways such as STAT3, transforming growth factors-β (TGF-β/Smad) and PI3K [ 12 , 32 , 34 – 37 ]. Upon injury, astrocytes undergo phenotypic and morphologic changes.…”