Pintado, CristinaMacías, SandraDomínguez-Martín, HelenaCastaño, AngélicaRuano, Diego2023-01-252023-01-252017-08-14http://hdl.handle.net/10668/11501Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD). We demonstrate that LPS injection induced autophagy activation that was dependent, at least in part, on glycogen synthase kinase (GSK)-3β activity but independent of mammalian target of rapamycin (mTOR) inhibition. Neuroinflammation also produced endoplasmic reticulum (ER) stress leading to canonical unfolded protein response (UPR) activation with a rapid activating transcription factor (ATF) 6α attenuation that resulted in a time-dependent down-regulation of ERAD markers. In this regard, the time-dependent accumulation of unspliced X-box binding protein (XBP) 1, likely because of decreased inositol-requiring enzyme (IRE) 1α-mediated splicing activity, might underlie in vivo ATF6α attenuation. Importantly, lactacystin-induced activation of ERAD was abolished in both the acute neuroinflammation model and in aged rats. Therefore, we provide a cellular pathway through which neuroinflammation might sensitize cells to neurodegeneration under stress situations, being relevant in normal aging and other disorders where neuroinflammation is a characteristic feature.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Activating Transcription Factor 6AnimalsAutophagyCell LineDown-RegulationEndoplasmic Reticulum StressEndoplasmic Reticulum-Associated DegradationEndoribonucleasesGlycogen Synthase Kinase 3 betaInflammationMaleMiceProteostasisRatsRats, WistarSignal TransductionTOR Serine-Threonine KinasesUnfolded Protein ResponseX-Box Binding Protein 1research article28808322open access10.1038/s41598-017-08722-32045-2322PMC5556015https://www.nature.com/articles/s41598-017-08722-3.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556015/pdf