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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

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

Authors: Avila, Jesus | Hernandez, Felix | Wandosell, Francisco | Lucas, Jose J. | Esteban, Jose A. | Ledesma, M. Dolores | Bullido, Maria J.

Article Type: Research Article

Abstract: One important aspect of studies carried out at the Center for Molecular Biology “Severo Ochoa” is focused on basic aspects of Alzheimer's disease, mainly the search for suitable therapeutic targets for this disorder. Several groups at the Center are involved in these studies, and, in this spotlight, the work they are carrying out will be described.

DOI: 10.3233/JAD-2010-100912

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 325-335, 2010

Authors: Rodrıguez-Rodrıguez, Eloy | Vázquez-Higuera, José Luis | Sánchez-Juan, Pascual | Mateo, Ignacio | Pozueta, Ana | Martínez-García, Ana | Frank, Ana | Valdivieso, Fernando | Berciano, José | Bullido, María J. | Combarros, Onofre

Article Type: Research Article

Abstract: Aberrant cholesterol metabolism has been implicated in Alzheimer's disease (AD). Recent findings have suggested an interaction of Niemann-Pick C1 (NPC1) and ATP-binding cassette transporter A1 (ABCA1) proteins in intracellular cholesterol transport and in maintaining cell cholesterol balance. Underexpression of NPC1 in concert with under-expression of ABCA1 would result in increased cholesterol accumulation and increased AD risk. We examined a functional polymorphism in the ABCA1 promoter region (-477, rs2422493), and four NPC1 polymorphisms in exon 6 (rs18050810), intron 20 (rs4800488), intron 22 (rs2236707), and intron 24 (rs2510344) capturing 85% of genetic variability in the Hap Map Caucasian (CEU) population, in a …group of 631 Spanish AD patients and 731 controls. Subjects carrying both the ABCA1 (-477) TT genotype and the NPC1 (exon 6) GG genotype (OR=1.89; 95% CI 1.04–3.41), NPC1 (intron 20) AA genotype (OR=2.05; 95% CI 1.26–3.33), NPC1 (intron 22) AA genotype (OR=2.05; 95% or NPC1 (intron 24) GG genotype (OR=1.89; 95% higher risk of developing AD than subjects without these risk genotypes. Testing for epistatic interaction between genes in the pathway of cholesterol metabolism might be useful for predicting AD risk. Show more

Keywords: ABCA1, Alzheimer's disease, cholesterol, epistasis, NPC1, polymorphism

DOI: 10.3233/JAD-2010-100432

Citation: Journal of Alzheimer's Disease, vol. 21, no. 2, pp. 619-625, 2010

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

Authors: Vázquez-Higuera, José Luis | Mateo, Ignacio | Sánchez-Juan, Pascual | Rodríguez-Rodríguez, Eloy | Pozueta, Ana | Calero, Miguel | Dobato, José Luis | Frank-García, Ana | Valdivieso, Fernando | Berciano, José | Bullido, Maria J. | Combarros, Onofre

Article Type: Research Article

Abstract: Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was …an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30–1.77; p = 1.24 × 10−5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10−5 ) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10−4 ) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset). Show more

Keywords: Alzheimer's disease, kinases, phosphorylation, polymorphism, tau

DOI: 10.3233/JAD-2011-110794

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 291-297, 2011

Authors: Belbin, Olivia | Morgan, Kevin | Medway, Chris | Warden, Donald | Cortina-Borja, Mario | van Duijn, Cornelia M. | Adams, Hieab H.H. | Frank-Garcia, Ana | Brookes, Keeley | Sánchez-Juan, Pascual | Alvarez, Victoria | Heun, Reinhard | Kölsch, Heike | Coto, Eliecer | Kehoe, Patrick G. | Rodriguez-Rodriguez, Eloy | Bullido, Maria J | Ikram, M. Arfan | Smith, A. David | Lehmann, Donald J.

Article Type: Research Article

Abstract: Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer’s disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF , DBH , and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern …Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1–1.2, p  = 0.005–0.3), an effect size that was consistent in the Northern European (OR = 1.1–1.2, p  = 0.002–0.8) but not the smaller Spanish (OR = 0.8–1.6, p  = 0.4–1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3–1.5 p  = 0.002–0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2–1.3, p  = 0.007–0.00008) than men (OR = 0.9–1.0, p  = 0.3–0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p  = 0.04) the synergistic interaction (SF = 2.2, p  = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p  = 0.04) than men (SF = 2.0, p  = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, dopamine beta-hydroxylase, epistasis, genetics, neurotrophins, Sortilin

DOI: 10.3233/JAD-181116

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1535-1547, 2019

Authors: Itzhaki, Ruth F. | Lathe, Richard | Balin, Brian J. | Ball, Melvyn J. | Bearer, Elaine L. | Braak, Heiko | Bullido, Maria J. | Carter, Chris | Clerici, Mario | Cosby, S. Louise | Del Tredici, Kelly | Field, Hugh | Fulop, Tamas | Grassi, Claudio | Griffin, W. Sue T. | Haas, Jürgen | Hudson, Alan P. | Kamer, Angela R. | Kell, Douglas B. | Licastro, Federico | Letenneur, Luc | Lövheim, Hugo | Mancuso, Roberta | Miklossy, Judith | Otth, Carola | Palamara, Anna Teresa | Perry, George | Preston, Christopher | Pretorius, Etheresia | Strandberg, Timo | Tabet, Naji | Taylor-Robinson, Simon D. | Whittum-Hudson, Judith A.

Article Type: Editorial

DOI: 10.3233/JAD-160152

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 979-984, 2016

Authors: Pastor, Pau | Moreno, Fermín | Clarimón, Jordi | Ruiz, Agustín | Combarros, Onofre | Calero, Miguel | de Munain, Adolfo López | Bullido, Maria J. | de Pancorbo, Marian M. | Carro, Eva | Antonell, Anna | Coto, Eliecer | Ortega-Cubero, Sara | Hernandez, Isabel | Tárraga, Lluís | Boada, Mercè | Lleó, Alberto | Dols-Icardo, Oriol | Kulisevsky, Jaime | Vázquez-Higuera, José Luis | Infante, Jon | Rábano, Alberto | Fernández-Blázquez, Miguel Ángel | Valentí, Meritxell | Indakoetxea, Begoña | Barandiarán, Myriam | Gorostidi, Ana | Frank-García, Ana | Sastre, Isabel | Lorenzo, Elena | Pastor, María A. | Elcoroaristizabal, Xabier | Lennarz, Martina | Maier, Wolfang | Rámirez, Alfredo | Serrano-Ríos, Manuel | Lee, Suzee E. | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer’s disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson’s disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p  = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p … = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ 4 noncarriers (OR = 1.14; p  = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p  = 0.0003) and PSP (OR = 3.18; p  = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ 4 AD. Show more

Keywords: A152T, Alzheimer’s disease, frontotemporal dementia, genetic association, H1H2, MAPT

DOI: 10.3233/JAD-150555

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 343-352, 2016

Authors: Lambert, Jean-Charles | Sleegers, Kristel | González-Pérez, Antonio | Ingelsson, Martin | Beecham, Gary W. | Hiltunen, Mikko | Combarros, Onofre | Bullido, Maria J. | Brouwers, Nathalie | Bettens, Karolien | Berr, Claudine | Pasquier, Florence | Richard, Florence | DeKosky, Steven T. | Hannequin, Didier | Haines, Jonathan L. | Tognoni, Gloria | Fiévet, Nathalie | Dartigues, Jean-François | Tzourio, Christophe | Engelborghs, Sebastiaan | Arosio, Beatrice | Coto, Elicer | De Deyn, Peter | Del Zompo, Maria | Mateo, Ignacio | Boada, Merce | Antunez, Carmen | Lopez-Arrieta, Jesus | Epelbaum, Jacques | Schjeide, Brit-Maren Michaud | Frank-Garcia, Ana | Giedraitis, Vilmentas | Helisalmi, Seppo | Porcellini, Elisa | Pilotto, Alberto | Forti, Paola | Ferri, Raffaele | Delepine, Marc | Zelenika, Diana | Lathrop, Mark | Scarpini, Elio | Siciliano, Gabriele | Solfrizzi, Vincenzo | Sorbi, Sandro | Spalletta, Gianfranco | Ravaglia, Giovanni | Valdivieso, Fernando | Vepsäläinen, Saila | Alvarez, Victoria | Bosco, Paolo | Mancuso, Michelangelo | Panza, Francesco | Nacmias, Benedetta | Bossù, Paola | Hanon, Olivier | Piccardi, Paola | Annoni, Giorgio | Mann, David | Marambaud, Philippe | Seripa, Davide | Galimberti, Daniela | Tanzi, Rudolph E | Bertram, Lars | Lendon, Corinne | Lannfelt, Lars | Licastro, Federico | Campion, Dominique | Pericak-Vance, Margaret A. | Soininen, Hilkka | Van Broeckhoven, Christine | Alpérovitch, Annick | Ruiz, Agustin | Kamboh, M. Ilyas | Amouyel, Philippe

Article Type: Research Article

Abstract: The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the ε4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta-analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant …of AD but may modulate age of onset by interacting with the effect of the ε4 allele of the APOE gene. Show more

Keywords: Age at onset, Alzheimer's disease, apolipoprotein E, CALHM1, polymorphism

DOI: 10.3233/JAD-2010-100933

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 247-255, 2010