A Free Radical-Generating System Regulates Amyloid Oligomers: Involvement of Cathepsin B
Authors: Llorente, Patricia | Kristen, Henrike | Sastre, Isabel | Toledano-Zaragoza, Ana | Aldudo, Jesús | Recuero, María | Bullido, María J.
Article Type: Research Article
Abstract: Amyloid-β (Aβ), a major component of senile plaques, is generated via the proteolysis of amyloid-β protein precursor (AβPP). This cleavage also produces AβPP fragment-derived oligomers which can be highly neurotoxic. AβPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer’s disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AβPP proteolysis (β-secretase activity) and Aβ clearance (Aβ degradative activity). The present work examines the effect …of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AβPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AβPP and secreted α -secretase-cleaved soluble AβPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS. Show more
Keywords: amyloid-β, amyloid-β protein precursor, cathepsin B, free radicals, oligomer, oxidative stress
DOI: 10.3233/JAD-170159
Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1397-1408, 2018
A Free Radical-Generating System Regulates AβPP Metabolism/Processing: Involvement of the Ubiquitin/Proteasome and Autophagy/Lysosome Pathways
Authors: Recuero, María | Munive, Victor A. | Sastre, Isabel | Aldudo, Jesús | Valdivieso, Fernando | Bullido, María J.
Article Type: Research Article
Abstract: Oxidative stress is an early event in the pathogenesis of Alzheimer's disease (AD). We previously reported that, in SK-N-MC cells, the xanthine/xanthine oxidase (X-XOD) free radical generating system regulates the metabolism/processing of the amyloid-β protein precursor (AβPP). Oxidative stress alters the two main cellular proteolytic machineries, the ubiquitin/proteasome (UPS) and the autophagy/lysosome systems, and recent studies have established connections between the malfunctioning of these and the pathogenesis of AD. The aim of the present work was to examine the involvement of these proteolytic systems in the regulation of AβPP metabolism by X-XOD. The proteasome inhibitor MG132 was found to accelerate …the metabolism/processing of AβPP promoted by X-XOD because it significantly enhances the secretion of α-secretase-cleaved soluble AβPP and also the levels of both carboxy-terminal fragments (CTFs) produced by α- and β-secretase. Further, MG132 modulated the intracellular accumulation of holo-AβPP and/or AβPP CTFs. This indicates that the X-XOD modulation of AβPP metabolism/processing involves the UPS pathway. With respect to the autophagy/lysosome pathway, the AβPP processing and intracellular location patterns induced by X-XOD treatment closely resembled those produced by the lysosome inhibitor ammonium chloride. The present results suggest that the regulation of AβPP metabolism/processing by mild oxidative stress requires UPS activity with a simultaneous reduction in that of the autophagy/lysosome system. Show more
Keywords: Alzheimer's disease, amyloid-β protein precursor, free radicals, lysosome, metabolism, oxidative stress, proteasome
DOI: 10.3233/JAD-121510
Citation: Journal of Alzheimer's Disease, vol. 34, no. 3, pp. 637-647, 2013
Herpes Simplex Virus Type I Induces an Incomplete Autophagic Response in Human Neuroblastoma Cells
Authors: Santana, Soraya | Bullido, Maria Jesús | Recuero, Maria | Valdivieso, Fernando | Aldudo, Jesus
Article Type: Research Article
Abstract: Autophagy is a homeostatic process involved in the turnover or elimination of cytoplasmic components, damaged organelles, and protein aggregates via a lysosomal degradation mechanism. Autophagy also provides a mechanism of innate immunity, known as xenophagy, designed to protect cells from intracellular pathogens, but it may unfortunately be subverted to act as a pro-viral pathway facilitating the replication of certain viruses. Herpes simplex virus type I (HSV-1) is a neurotropic virus that remains latent in host neurons; it is the most common cause of sporadic viral encephalitis. Moreover, HSV-1 has been related to the pathogenesis of Alzheimer's disease. HSV-1 can modulate …the autophagic process through a mechanism mediated by the viral protein ICP34.5. Here we report that HSV-1 induces a strong increase in GFP-LC3 and endogenous LC3 lipidation, and triggers the accumulation of intracellular autophagic compartments (mainly autophagosomes) without enhancing autophagic long-lived protein degradation in the late stages of infection. Autophagy inhibition mediated by ATG5 gene silencing had no effect on viral growth. The present results suggest that HSV-1 infection activates the host autophagic machinery and strongly controls the autophagic process, blocking the fusion of autophagosomes with lysosomes. These events might be important in the neurodegenerative process associated with HSV-1 infection. Show more
Keywords: ATG5, autophagy, HSV-1, LC3, lysosome, neurodegeneration
DOI: 10.3233/JAD-2012-112000
Citation: Journal of Alzheimer's Disease, vol. 30, no. 4, pp. 815-831, 2012
PLA2G3, a Gene Involved in Oxidative Stress Induced Death, is Associated with Alzheimer's Disease
Authors: Martínez-García, Ana | Sastre, Isabel | Recuero, María | Aldudo, Jesús | Vilella, Elisabet | Mateo, Ignacio | Sánchez-Juan, Pascual | Vargas, Teo | Carro, Eva | Bermejo-Pareja, Félix | Rodríguez-Rodríguez, Eloy | Combarros, Onofre | Rosich-Estrago, Marcel | Frank, Ana | Valdivieso, Fernando | Bullido, María J.
Article Type: Research Article
Abstract: Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging, the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking such stress in AD brains, are therefore of great interest. PLA2G3 is the most overexpressed gene in a human neuronal model of oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system, which provokes apoptotic cell death. In this work, we describe that PLA2G3 gene silencing produced a marked inhibition of X-XOD induced cell death, and that PLA2G3 polymorphisms are …associated with AD in a Spanish case-control sample. The capacity to respond to oxidative stress may therefore modulate the risk of AD, and PLA2G3 is a potential target to regulate neuronal damage induced by free radicals. Show more
Keywords: Alzheimer's disease, cell injury, genetic association, neurodegeneration, oxidative stress, PLA2G3
DOI: 10.3233/JAD-2010-101348
Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1181-1187, 2010