Person: Urdánoz Casado, Amaya
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Urdánoz Casado
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Amaya
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Ciencias de la Salud
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0000-0002-6312-8330
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123923
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Publication Open Access Profile of TREM2-derived circRNA and mRNA variants in the entorhinal cortex of Alzheimer's disease patients(MDPI, 2022) Urdánoz Casado, Amaya; Sánchez Ruiz de Gordoa, Javier; Robles, Maitane; Roldán, Miren; Zelaya Huerta, María Victoria; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaGenetic variants in TREM2, a microglia-related gene, are well-known risk factors for Alzheimer’s disease (AD). Here, we report that TREM2 originates from circular RNAs (circRNAs), a novel class of non-coding RNAs characterized by a covalent and stable closed-loop structure. First, divergent primers were designed to amplify circRNAs by RT-PCR, which were further assessed by Sanger sequencing. Then, additional primer sets were used to confirm back-splicing junctions. In addition, HMC3 cells were used to assess the microglial expression of circTREM2s. Three candidate circTREM2s were identified in control and AD human entorhinal samples. One of the circRNAs, circTREM2_1, was consistently amplified by all divergent primer sets in control and AD entorhinal cortex samples as well as in HMC3 cells. In AD cases, a moderate negative correlation (r = −0.434) was found between the global average area of Aβ deposits in the entorhinal cortex and circTREM2_1 expression level. In addition, by bioinformatics tools, a total of 16 miRNAs were predicted to join with circTREM2s. Finally, TREM2 mRNA corresponding to four isoforms was profiled by RTqPCR. TREM2 mRNA levels were found elevated in entorhinal samples of AD patients with low or intermediate ABC scores compared to controls. To sum up, a novel circRNA derived from the TREM2 gene, circTREM2_1, has been identified in the human entorhinal cortex and TREM2 mRNA expression has been detected to increase in AD compared to controls. Unraveling the molecular genetics of the TREM2 gene may help to better know the innate immune response in AD.Publication Open Access Gender-dependent deregulation of linear and circular RNA variants of homer1 in the entorhinal cortex of Alzheimer’s disease(MDPI, 2021) Urdánoz Casado, Amaya; Sánchez Ruiz de Gordoa, Javier; Robles Solano, Maitane; Acha Santamaría, Blanca; Roldán, Miren; Zelaya Huerta, María Victoria; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaThe HOMER1 gene is involved in synaptic plasticity, learning and memory. Recent studies show that circular RNA derived from HOMER1 (circHOMER1) expression is altered in some Alzheimer’s disease (AD) brain regions. In addition, HOMER1 messenger (mRNA) levels have been associated with β-Amyloid (Aβ) deposits in brain cortical regions. Our aim was to measure the expression levels of HOMER1 circRNAs and their linear forms in the human AD entorhinal cortex. First, we showed downregulation of HOMER1B/C and HOMER1A mRNA and hsa_circ_0006916 and hsa_circ_0073127 levels in AD female cases compared to controls by RT-qPCR. A positive correlation was observed between HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073128 with HOMER1B/C protein only in females. Global average area of Aβ deposits in entorhinal cortex samples was negatively correlated with HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073127 in both genders. Furthermore, no differences in DNA methylation were found in two regions of HOMER1 promoter between AD cases and controls. To sum up, we demonstrate that linear and circular RNA variants of HOMER1 are downregulated in the entorhinal cortex of female patients with AD. These results add to the notion that HOMER1 and its circular forms could be playing a female-specific role in the pathogenesis of AD.Publication Open Access Liquid biopsy in alzheimer's disease patients reveals epigenetic changes in the PRLHR gene(MDPI, 2023) Macías, Mónica; Acha Santamaría, Blanca; Corroza, Jon; Urdánoz Casado, Amaya; Roldán, Miren; Robles, Maitane; Sánchez Ruiz de Gordoa, Javier; Erro Aguirre, María Elena; Jericó Pascual, Ivonne; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun ZientziakIn recent years, new DNA methylation variants have been reported in genes biologically relevant to Alzheimer’s disease (AD) in human brain tissue. However, this AD-specific epigenetic information remains brain-locked and unreachable during patients’ lifetimes. In a previous methylome performed in the hippocampus of 26 AD patients and 12 controls, we found higher methylation levels in AD patients in the promoter region of PRLHR, a gene involved in energy balance regulation. Our aim was to further characterize PRLHR’s role in AD and to evaluate if the liquid biopsy technique would provide life access to this brain information in a non-invasive way. First, we extended the methylation mapping of PRLHR and validated previous methylome results via bisulfite cloning sequencing. Next, we observed a positive correlation between PRLHR methylation levels and AD-related neuropathological changes and a decreased expression of PRLHR in AD hippocampus. Then, we managed to replicate the hippocampal methylation differences in plasma cfDNA from an additional cohort of 35 AD patients and 35 controls. The isolation of cfDNA from the plasma of AD patients may constitute a source of potential epigenetic biomarkers to aid AD clinical management.Publication Open Access NXN gene epigenetic changes in an adult neurogenesis model of Alzheimer's disease(MDPI, 2022) Blanco Luquin, Idoia; Acha Santamaría, Blanca; Urdánoz Casado, Amaya; Gómez Orte, Eva; Roldán, Miren; Pérez Rodríguez, Diego R.; Cabello, Juan; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaIn view of the proven link between adult hippocampal neurogenesis (AHN) and learning and memory impairment, we generated a straightforward adult neurogenesis in vitro model to recapitulate DNA methylation marks in the context of Alzheimer’s disease (AD). Neural progenitor cells (NPCs) were differentiated for 29 days and Aβ peptide 1–42 was added. mRNA expression of Neuronal Differentiation 1 (NEUROD1), Neural Cell Adhesion Molecule 1 (NCAM1), Tubulin Beta 3 Class III (TUBB3), RNA Binding Fox-1 Homolog 3 (RBFOX3), Calbindin 1 (CALB1), and Glial Fibrillary Acidic Protein (GFAP) was determined by RT-qPCR to characterize the culture and framed within the multistep process of AHN. Hippocampal DNA methylation marks previously identified in Contactin-Associated Protein 1 (CNTNAP1), SEPT5-GP1BB Readthrough (SEPT5-GP1BB), T-Box Transcription Factor 5 (TBX5), and Nucleoredoxin (NXN) genes were profiled by bisulfite pyrosequencing or bisulfite cloning sequencing; mRNA expression was also measured. NXN outlined a peak of DNA methylation overlapping type 3 neuroblasts. Aβ-treated NPCs showed transient decreases of mRNA expression for SEPT5-GP1BB and NXN on day 9 or 19 and an increase in DNA methylation on day 29 for NXN. NXN and SEPT5-GP1BB may reflect alterations detected in the brain of AD human patients, broadening our understanding of this disease.Publication Open Access Association of blood-based DNA methylation markers with late-onset alzheimer disease: a potential diagnostic approach(Lippincott Williams & Wilkins, 2023) Acha Santamaría, Blanca; Corroza, Jon; Sánchez Ruiz de Gordoa, Javier; Cabello, Carolina; Robles Solano, Maitane; Méndez López, Iván; Macías, Mónica; Zueco, Sara; Roldán, Miren; Urdánoz Casado, Amaya; Jericó Pascual, Ivonne; Erro Aguirre, María Elena; Alcolea, Daniel; Lleo, Alberto; Blanco Luquin, Idoia; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun ZientziakBackground and Objectives: There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls. Methods: A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with “probable AD dementia” following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex. Results: The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at NXN, ABCA7, and HOXA3 genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89–0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and APOE ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, HOXA3 DNA methylation levels showed consistent association with AD. Discussion: These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD. Registration Information: Research Ethics Committee of the University Hospital of Navarre (PI17/02218).Publication Open Access Telomere length correlates with subtelomeric DNA methylation in long-term mindfulness practitioners(Nature Research, 2020) Mendióroz Iriarte, Maite; Puebla Guedea, Marta; Montero Marín, Jesús; Urdánoz Casado, Amaya; Labarga Gutiérrez, Alberto; Ciencias de la Salud; Osasun ZientziakMindfulness and meditation techniques have proven successful for the reduction of stress and improvement in general health. In addition, meditation is linked to longevity and longer telomere length, a proposed biomarker of human aging. Interestingly, DNA methylation changes have been described at specific subtelomeric regions in long-term meditators compared to controls. However, the molecular basis underlying these beneficial effects of meditation on human health still remains unclear. Here we show that DNA methylation levels, measured by the Infinium HumanMethylation450 BeadChip (Illumina) array, at specific subtelomeric regions containing GPR31 and SERPINB9 genes were associated with telomere length in long-term meditators with a strong statistical trend when correcting for multiple testing. Notably, age showed no association with telomere length in the group of long-term meditators. These results may suggest that long-term meditation could be related to epigenetic mechanisms, in particular gene-specific DNA methylation changes at distinct subtelomeric regions.Publication Open Access Early epigenetic changes of Alzheimer's disease in the human hippocampus(2020) Blanco Luquin, Idoia; Acha Santamaría, Blanca; Urdánoz Casado, Amaya; Sánchez Ruiz de Gordoa, Javier; Vicuña-Urriza, Janire; Roldán, Miren; Labarga Gutiérrez, Alberto; Zelaya Huerta, María Victoria; Cabello, Carolina; Méndez López, Iván; Mendióroz Iriarte, Maite; Ciencias de la Salud; Osasun Zientziak; Sociología y Trabajo Social; Soziologia eta Gizarte Lana; Gobierno de Navarra / Nafarroako GobernuaThe discovery of new biomarkers would be very valuable to improve the detection of early Alzheimer's disease (AD). DNA methylation marks may serve as epigenetic biomarkers of early AD. Here we identified epigenetic marks that are present in the human hippocampus from the earliest stages of AD. A previous methylome dataset of the human AD hippocampus was used to select a set of eight differentially methylated positions (DMPs) since early AD stages. Next, bisulphite pyrosequencing was performed in an expanded homogeneous cohort of 18 pure controls and 35 hippocampal samples with neuropathological changes of pure AD. Correlation between DNA methylation levels in DMPs and phospho-tau protein burden assessed by immunohistochemistry in the hippocampus was also determined. We found four DMPs showing higher levels of DNA methylation at early AD stages compared to controls, involving ELOVL2, GIT1/TP53I13 and the histone gene locus at chromosome 6. DNA methylation levels assessed by bisulphite pyrosequencing correlated with phospho-tau protein burden for ELOVL2 and HIST1H3E/HIST1H3 F genes. In this discovery study, a set of four epigenetic marks of early AD stages have been identified in the human hippocampus. It would be worth studying in-depth the specific pathways related to these epigenetic marks. These early alterations in DNA methylation in the AD hippocampus could be regarded as candidate biomarkers to be explored in future translational studies.