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1. The local/logarithmic correspondence and the degeneration formula for quasimaps

Author

Rabano, Alberto Cobos, Manolache, Cristina, and Shafi, Qaasim

Subjects
Mathematics - Algebraic Geometry, 14N35, 14D06, 14A21
Abstract

We study the relationship between the enumerative geometry of rational curves in local geometries and various versions of maximal contact logarithmic curve counts. Our approach is via quasimap theory, and we show versions of the arXiv:1712.05210 local/logarithmic correspondence for quasimaps, and in particular for normal crossings settings, where the Gromov-Witten theoretic formulation of the correspondence fails. The results suggest a link between different formulations of relative Gromov-Witten theory for simple normal crossings divisors via the mirror map. The main results follow from a rank reduction strategy, together with a new degeneration formula for quasimaps., Comment: 37 pages, 4 figures, comments welcome

Published
2024

2. Desingularizations of sheaves and higher genus reduced Gromov-Witten invariants

Author

Rabano, Alberto Cobos, Mann, Etienne, Manolache, Cristina, and Picciotto, Renata

Subjects
Mathematics - Algebraic Geometry, 14N35 (Primary) 14A20 (Secondary)
Abstract

Given $\mathfrak{F}$ a coherent sheaf on a Noetherian integral algebraic stack $\mathfrak{P}$, we give two constructions of stacks $\widetilde{\mathfrak{P}}$, equipped with birational morphisms $p:\widetilde{\mathfrak{P}}\to \mathfrak{P}$ such that $p^*\mathfrak{F}$ is simpler: in the Rossi construction, the torsion free part of $p^*\mathfrak{F}$ is locally free; in the Hu--Li diagonalization construction, $p^*\mathfrak{F}$ is a union of locally free sheaves. We use these constructions to define reduced Gromov--Witten invariants of a large class of GIT quotients in all genera., Comment: 81 pages. Exposition has been improved and the main construction has been generalized. Comments welcome

Published
2023

3. Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

Author

Hopfner, Franziska, Tietz, Anja, Ruf, Viktoria, Ross, Owen, Koga, Shunsuke, Dickson, Dennis, Aguzzi, Adriano, Attems, Johannes, Beach, Thomas, Beller, Allison, Cheshire, William, van Deerlin, Vivianna, Deuschl, Günther, Duyckaerts, Charles, Ellinghaus, David, Evsyukov, Valentin, Flanagan, Margaret, Franke, Andre, Frosch, Matthew, Gearing, Marla, Gelpi, Ellen, van Gerpen, Jay, Ghetti, Bernardino, Glass, Jonathan, Halliday, Glenda, Helbig, Ingo, Höllerhage, Matthias, Huitinga, Inge, Irwin, David, Keene, Dirk, Kovacs, Gabor, Lee, Edward, Levin, Johannes, Martí, Maria, Mackenzie, Ian, McKeith, Ian, Mclean, Catriona, Mollenhauer, Brit, Neumann, Manuela, Newell, Kathy, Pantelyat, Alex, Pendziwiat, Manuela, Peters, Annette, Molina Porcel, Laura, Rabano, Alberto, Matěj, Radoslav, Rajput, Alex, Rajput, Ali, Reimann, Regina, Scott, William, Selvackadunco, Sashika, Simuni, Tanya, Stadelmann, Christine, Svenningsson, Per, Thomas, Alan, Trenkwalder, Claudia, Troakes, Claire, Trojanowski, John, Uitti, Ryan, White, Charles, Wszolek, Zbigniew, Xie, Tao, Ximelis, Teresa, Yebenes, Justo, Müller, Ulrich, Schellenberg, Gerard, Herms, Jochen, Kuhlenbäumer, Gregor, Höglinger, Günter, Grinberg, Lea, Seeley, William, and Desplats, Paula

Subjects
ZIC1, ZIC4, autopsy-confirmed, genome-wide association study, multiple system atrophy, Autoantibodies, Autopsy, Genome-Wide Association Study, Humans, Multiple System Atrophy, Nerve Tissue Proteins, Olivopontocerebellar Atrophies, Striatonigral Degeneration, Transcription Factors, alpha-Synuclein
Abstract

BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2022

4. A murine model of BSCL2-associated Celia's encephalopathy

Author

Cobelo-Gómez, Silvia, Sánchez-Iglesias, Sofía, Rábano, Alberto, Senra, Ana, Aguiar, Pablo, Gómez-Lado, Noemí, García-Varela, Lara, Burgueño-García, Iván, Lampón-Fernández, Laura, Fernández-Pombo, Antía, Díaz-López, Everardo Josué, Prado-Moraña, Teresa, San Millán, Beatriz, and Araújo-Vilar, David

Published
2023
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5. Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights.

Author

Pérez‐Oliveira, Sergio, Castilla‐Silgado, Juan, Painous, Cèlia, Aldecoa, Iban, Menéndez‐González, Manuel, Blázquez‐Estrada, Marta, Corte, Daniela, Tomás‐Zapico, Cristina, Compta, Yaroslau, Muñoz, Esteban, Lladó, Albert, Balasa, Mircea, Aragonès, Gemma, García‐González, Pablo, Rosende‐Roca, Maitée, Boada, Mercè, Ruíz, Agustín, Pastor, Pau, De la Casa‐Fages, Beatriz, and Rabano, Alberto

Subjects
TAUOPATHIES, PROGRESSIVE supranuclear palsy, ALZHEIMER'S disease, HUNTINGTON disease, NEURODEGENERATION
Abstract

Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies. [ABSTRACT FROM AUTHOR]

Published
2024
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8. PSP/DEGESCO: A Progressive Supranuclear Palsy Genome‐Wide Association Study in the Spanish Population

Author

García‐González, Pablo, primary, de Rojas, Itziar, additional, Rabano, Alberto, additional, Bullido, María J., additional, Puerta, Raquel, additional, Olivé, Clàudia, additional, Álvarez‐Martínez, Victoria, additional, Perez‐Tur, Jordi, additional, Mendioroz, Maite, additional, Fortuño, Maria Antonia, additional, Belbin, Olivia, additional, Compta, Yaroslau, additional, Sanchez‐Juan, Pascual, additional, Tárraga, Lluís, additional, Boada, Mercè, additional, and Ruiz, Agustin, additional

Published
2023
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11. Genetic dissection of Hippocampal sclerosis MRI surrogates

Author

Olivé, Clàudia, primary, de Rojas, Itziar, additional, Zhang, Linda, additional, Sotolongo‐Grau, Oscar, additional, Quintela, Inés, additional, García‐González, Pablo, additional, García‐Sánchez, Ainhoa, additional, Puerta, Raquel, additional, Valero, Sergi, additional, Cano, Amanda, additional, Calero, Miguel, additional, Rabano, Alberto, additional, Pastor, Ana Belén, additional, Ser, Teodoro, additional, Medina, Miguel, additional, Sanchez‐Juan, Pascual, additional, Strange, Bryan A, additional, Carracedo, Angel, additional, Marquié, Marta, additional, Tárraga, Lluís, additional, Boada, Mercè, additional, and Ruiz, Agustin, additional

Published
2023
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12. Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

Author

Alvarez-Vergara, Maria I., Rosales-Nieves, Alicia E., March-Diaz, Rosana, Rodriguez-Perinan, Guiomar, Lara-Ureña, Nieves, Ortega-de San Luis, Clara, Sanchez-Garcia, Manuel A., Martin-Bornez, Miguel, Gómez-Gálvez, Pedro, Vicente-Munuera, Pablo, Fernandez-Gomez, Beatriz, Marchena, Miguel A., Bullones-Bolanos, Andrea S., Davila, Jose C., Gonzalez-Martinez, Rocio, Trillo-Contreras, Jose L., Sanchez-Hidalgo, Ana C., del Toro, Raquel, Scholl, Francisco G., Herrera, Eloisa, Trepel, Martin, Körbelin, Jakob, Escudero, Luis M., Villadiego, Javier, Echevarria, Miriam, de Castro, Fernando, Gutierrez, Antonia, Rabano, Alberto, Vitorica, Javier, and Pascual, Alberto

Published
2021
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13. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

Author

Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Corbatón, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García González, P., Gil, S., Guitart, M., González Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M.T., Marquié, M., Mauleón, A., Monté-Rubio, G., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejà, E., Pérez-Cordon, A., Pineda, J.A., Preckler, S., Quintela, I., Real, L.M., Rodríguez-Gómez, O., Rosende-Roca, M., Ruiz, A., Ruiz, S., Sáez, M.E., Sanabria, A., Santos-Santos, M.A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A.D., Alarcón-Martín, E., Álvarez, I., Álvarez, V., Amer-Ferrer, Goo, Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Buiza-Rueda, D., Bullido, M.J., Burguera, J.A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., del Ser, T., Diez-Fairen, M., Fortea, J., Franco, E., Frank-García, A., García-Alberca, J.M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Espinosa, Labrador, Lage, C., Legaz, A., Lleó, A., López de Munáin, A., López-García, S., Macias, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J.L., Pastor, A.B., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Piñol Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J.L., A, Ruiz, Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vivancos, L., Moreno-Grau, Sonia, de Rojas, Itziar, Hernández, Isabel, Quintela, Inés, Montrreal, Laura, Alegret, Montserrat, Hernández-Olasagarre, Begoña, Madrid, Laura, González-Perez, Antonio, Maroñas, Olalla, Rosende-Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Lafuente, Asunción, Abdelnour, Carla, Rodríguez-Gómez, Octavio, Gil, Silvia, Santos-Santos, Miguel Ángel, Espinosa, Ana, Ortega, Gemma, Sanabria, Ángela, Pérez-Cordón, Alba, Cañabate, Pilar, Moreno, Mariola, Preckler, Silvia, Ruiz, Susana, Aguilera, Nuria, Pineda, Juan Antonio, Macías, Juan, Alarcón-Martín, Emilio, Sotolongo-Grau, Oscar, Marquié, Marta, Monté-Rubio, Gemma, Valero, Sergi, Benaque, Alba, Clarimón, Jordi, Bullido, Maria Jesus, García-Ribas, Guillermo, Pástor, Pau, Sánchez-Juan, Pascual, Álvarez, Victoria, Piñol-Ripoll, Gerard, García-Alberca, Jose Maria, Royo, José Luis, Franco, Emilio, Mir, Pablo, Calero, Miguel, Medina, Miguel, Rábano, Alberto, Ávila, Jesús, Antúnez, Carmen, Real, Luis Miguel, Orellana, Adelina, Carracedo, Ángel, Sáez, María Eugenia, Tárraga, Lluís, Boada, Mercè, and Ruiz, Agustín

Published
2019
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15. DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease

Author

Sanchez-Mut, Jose V., Aso, Ester, Panayotis, Nicolas, Lott, Ira, Dierssen, Mara, Rabano, Alberto, Urdinguio, Rocio G., Fernandez, Agustin F., Astudillo, Aurora, Martin-Subero, Jose I., Balint, Balazs, Fraga, Mario F., Gomez, Antonio, Gurnot, Cecile, Roux, Jean-Christophe, Avila, Jesus, Hensch, Takao K., Ferrer, Isidre, and Esteller, Manel

Abstract

The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer’s disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5’-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer’s disease. We were able to translate these findings to patients with Alzheimer’s disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.

Published
2013

19. The human olfactory system in two proteinopathies: Alzheimer’s and Parkinson’s diseases

Author

Ubeda-Bañon, Isabel, Saiz-Sanchez, Daniel, Flores-Cuadrado, Alicia, Rioja-Corroto, Ernesto, Gonzalez-Rodriguez, Melania, Villar-Conde, Sandra, Astillero-Lopez, Veronica, Cabello-de la Rosa, Juan Pablo, Gallardo-Alcañiz, Maria Jose, Vaamonde-Gamo, Julia, Relea-Calatayud, Fernanda, Gonzalez-Lopez, Lucia, Mohedano-Moriano, Alicia, Rabano, Alberto, and Martinez-Marcos, Alino

Published
2020
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22. A murine model of BSCL2-associated Celia's encephalopathy

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Rabano, Alberto, Burgueño-García, Iván, Lampón-Fernández, Laura, Díaz-López, Everardo Josué, Prado-Moraña, Teresa, San Millán, Beatriz, Cobelo Gómez, Silvia, Sánchez Iglesias, Sofía, Senra, Ana, Aguiar, Pablo, Gómez Lado, Noemí, García Varela, Lara, Fernández-Pombo, Antía, Araújo-Vilar, David, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Rabano, Alberto, Burgueño-García, Iván, Lampón-Fernández, Laura, Díaz-López, Everardo Josué, Prado-Moraña, Teresa, San Millán, Beatriz, Cobelo Gómez, Silvia, Sánchez Iglesias, Sofía, Senra, Ana, Aguiar, Pablo, Gómez Lado, Noemí, García Varela, Lara, Fernández-Pombo, Antía, and Araújo-Vilar, David

Abstract

Celia's encephalopathy or progressive encephalopathy with/without lipodystrophy is a neurodegenerative disease with a fatal prognosis in childhood. It is generally caused by the c.985C > T variant in the BSCL2 gene, leading to the skipping of exon 7 and resulting in an aberrant seipin protein (Celia-seipin). To precisely define the temporal evolution and the mechanisms involved in neurodegeneration, lipodystrophy and fatty liver in Celia's encephalopathy, our group has generated the first global knock-in murine model for the aberrant human transcript of BSCL2 (Bscl2Celia/Celia) using a strategy based on the Cre/loxP recombination system. In order to carry out a characterization at the neurological, adipose tissue and hepatic level, behavioral studies, brain PET, metabolic, histological and molecular studies were performed. Around 12% of homozygous and 5.4% of heterozygous knock-in mice showed severe neurological symptoms early in life, and their life expectancy was dramatically reduced. Severe generalized lipodystrophy and mild hepatic steatosis were present in these affected animals, while serum triglycerides and glucose metabolism were normal, with no insulin resistance. Furthermore, the study revealed a reduction in brain glucose uptake, along with patchy loss of Purkinje cells and the presence of intranuclear inclusions in cerebellar cortex cells. Homozygous, non-severely-affected knock-in mice showed a decrease in locomotor activity and greater anxiety compared with their wild type littermates. Bscl2Celia/Celia is the first murine model of Celia's encephalopathy which partially recapitulates the phenotype and severe neurodegenerative picture suffered by these patients. This model will provide a helpful tool to investigate both the progressive encephalopathy with/without lipodystrophy and congenital generalized lipodystrophy.

Published
2023

23. Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior.

Author

Ortega‐Cruz, Diana, Iglesias, Juan Eugenio, Rabano, Alberto, and Strange, Bryan A.

Abstract

Introduction: Hippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically‐defined features is unknown. We investigated pre‐mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia‐associated pathologies. Methods: We analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow‐up and post‐mortem neuropathological evaluation, including HS assessment in the hippocampal head and body. Results: Significant HS‐associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy. Discussion: HS‐associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD. HIGHLIGHTS: Hippocampal atrophy was found in HS+ patients earlier than 10 years before death.These early pre‐mortem changes were driven by reduced CA1 and subiculum volumes.Rates of hippocampus and subfield volume decline were independent of HS.In contrast, steeper atrophy rates were associated with AD pathology burden.Differentiation between AD and HS could be facilitated based on these MRI findings. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Similarities of variant Creutzfeldt-Jakob disease strain in mother and son in Spain to UK reference case

Author

Diack, Abigail B., Boyle, Aileen, Ritchie, Diane, Plinston, Chris, Kisielewski, Dorothy, de Pedro-Cuesta, Jesus, Rabano, Alberto, Will, Robert G., and Manson, Jean C.

Subjects
Disease transmission -- Models, Creutzfeldt-Jakob disease -- Development and progression -- Care and treatment, Maternal-fetal exchange -- Health aspects, Heredity -- Health aspects, Health
Abstract

In 2008 in Spain. 2 cases of variant Creutzfeldt-Jakob disease (vCJD) in first-degree relatives were identified. After the death of a 41-year-old man (patient 1) from vCJD, Iiis 64-year-old mother [...]

Published
2017
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30. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

Author

Naranjo, Jose R., Zhang, Hongyu, Villar, Diego, Gonzalez, Paz, Dopazo, Xose M., Moron-Oset, Javier, Higueras, Elena, Oliveros, Juan C., Arrabal, Maria D., Prieto, Angela, Cercos, Pilar, Gonzalez, Teresa, De la Cruz, Alicia, Casado-Vela, Juan, Rabano, Alberto, Valenzuela, Carmen, Gutierrez-Rodriguez, Marta, Li, Jia-Yi, and Mellstrom, Britt

Subjects
Huntington's chorea -- Analysis -- Genetic aspects -- Development and progression, Cellular signal transduction -- Health aspects -- Genetic aspects, Transcription factors -- Health aspects, Health care industry
Abstract

Deregulated protein and [Ca.sup.2+] homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional [Ca.sup.2+]-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD., Introduction Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no cure, caused by the expansion of CAG triplets in the huntingtin (HTT) gene. As in other [...]

Published
2016
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31. New insights into the genetic etiology of Alzheimer's disease and related dementias

Author

Bellenguez, Celine, Kucukali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, De Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcon-Martin, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Alvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antunez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belen, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Celine, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Merce, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossu, Paola, Brathen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Ignacio Brusco, Luis, Buiza-Rueda, Dolores, Burger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Genevieve, Chung, Jaeyoon, Cuccaro, Michael L., Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. H. R., Clark, Christopher, Conti, Elisa, Corma-Gomez, Anais, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-Francois, de Deyn, Peter Paul, Lopes, Katia de Paiva, De Witte, Lot D., Debette, Stephanie, Deckert, Jurgen, del Ser, Teodoro, Denning, Nicola, Destefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Monica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Duzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernandez-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fliessbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macias, Emlio, Bullido, Maria J., Frank-Garcia, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, Maria Garcia-Alberca, Jose, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, Gonzalez-Perez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grunblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernandez, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Huerto Vilas, Raquel, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Stahlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleo, Alberto, Longstreth, William, Jr., Lopez, Oscar, Lopez de Munain, Adolfo, Love, Seth, Lowemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macias, Juan, Macleod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquie, Marta, Marshall, Rachel, Martin, Eden R., Martin Montes, Angel, Martinez Rodriguez, Carmen, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menendez-Gonzalez, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nothen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Borge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Perez-Cordon, Alba, Perez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. L., Pineda, Juan A., Pinol-Ripoll, Gerard, Pisanu, Laudia, Polak, Thomas, Popp, Julius, Posthuma, Danielle, Priller, Josef, Puerta, Raquel, Quenez, Olivier, Quintela, Ines, Thomassen, Jesper Qvist, Rabano, Alberto, Rainero, Innocenzo, Rajabli, Farid, Ramakers, Inez, Real, Luis M., Reinders, Marcel J. T., Reitz, Christiane, Reyes-Dumeyer, Dolly, Ridge, Perry, Riedel-Heller, Steffi, Riederer, Peter, Roberto, Natalia, Rodriguez-Rodriguez, Eloy, Rongve, Arvid, Rosas Allende, Irene, Rosende-Roca, Maitee, Luis Royo, Jose, Rubino, Elisa, Rujescu, Dan, Eugenia Saez, Maria, Sakka, Paraskevi, Saltvedt, Ingvild, Bernal Sanchez-Arjona, Maria, Sanchez-Garcia, Florentino, Sanchez Juan, Pascual, Sanchez-Valle, Raquel, Sando, Sigrid B., Sarnowski, Chloe, Satizabal, Claudia L., Scamosci, Michela, Scarmeas, Nikolaos, Scarpini, Elio, Scheltens, Philip, Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias, Schneider, Anja, Schott, Jonathan M., Selbaek, Geir, Seripa, Davide, Serrano, Manuel, Sha, Jin, Shadrin, Alexey A., Skrobot, Olivia, Slifer, Susan, Snijders, Gijsje J. L., Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Song, Yeunjoo, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Pablo Tartan, Juan, Tarraga, Lluis, Tesi, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tosto, Giuseppe, Traykov, Latchezar, Tremolizzo, Lucio, Tybjaerg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Valladares, Otto, Van Broeckhoven, Christine, Vance, Jeffery, Vardarajan, Badri N., van der Lugt, Aad, Van Dongen, Jasper, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sebastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Wang, Li-San, Wang, Ruiqi, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zare, Habil, Zhao, Yi, Zhang, Xiaoling, Zhu, Congcong, Zulaica, Miren, Farrer, Lindsay A., Psaty, Bruce M., Ghanbari, Mohsen, Raj, Towfique, Sachdev, Perminder, Mather, Karen, Jessen, Frank, Ikram, M. Arfan, de Mendonca, Alexandre, Hort, Jakub, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-Francois, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustin, Ramirez, Alfredo, Lambert, Jean-Charles, Bellenguez, Celine, Kucukali, Fahri, Jansen, Iris E., Kleineidam, Luca, Moreno-Grau, Sonia, Amin, Najaf, Naj, Adam C., Campos-Martin, Rafael, Grenier-Boley, Benjamin, Andrade, Victor, Holmans, Peter A., Boland, Anne, Damotte, Vincent, van der Lee, Sven J., Costa, Marcos R., Kuulasmaa, Teemu, Yang, Qiong, De Rojas, Itziar, Bis, Joshua C., Yaqub, Amber, Prokic, Ivana, Chapuis, Julien, Ahmad, Shahzad, Giedraitis, Vilmantas, Aarsland, Dag, Garcia-Gonzalez, Pablo, Abdelnour, Carla, Alarcon-Martin, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Alvarez, Victoria, Armstrong, Nicola J., Tsolaki, Anthoula, Antunez, Carmen, Appollonio, Ildebrando, Arcaro, Marina, Archetti, Silvana, Arias Pastor, Alfonso, Arosio, Beatrice, Athanasiu, Lavinia, Bailly, Henri, Banaj, Nerisa, Baquero, Miquel, Barral, Sandra, Beiser, Alexa, Pastor, Ana Belen, Below, Jennifer E., Benchek, Penelope, Benussi, Luisa, Berr, Claudine, Besse, Celine, Bessi, Valentina, Binetti, Giuliano, Bizarro, Alessandra, Blesa, Rafael, Boada, Merce, Boerwinkle, Eric, Borroni, Barbara, Boschi, Silvia, Bossu, Paola, Brathen, Geir, Bressler, Jan, Bresner, Catherine, Brodaty, Henry, Brookes, Keeley J., Ignacio Brusco, Luis, Buiza-Rueda, Dolores, Burger, Katharina, Burholt, Vanessa, Bush, William S., Calero, Miguel, Cantwell, Laura B., Chene, Genevieve, Chung, Jaeyoon, Cuccaro, Michael L., Cecchetti, Roberta, Cervera-Carles, Laura, Charbonnier, Camille, Chen, Hung-Hsin, Chillotti, Caterina, Ciccone, Simona, Claassen, Jurgen A. H. R., Clark, Christopher, Conti, Elisa, Corma-Gomez, Anais, Costantini, Emanuele, Custodero, Carlo, Daian, Delphine, Dalmasso, Maria Carolina, Daniele, Antonio, Dardiotis, Efthimios, Dartigues, Jean-Francois, de Deyn, Peter Paul, Lopes, Katia de Paiva, De Witte, Lot D., Debette, Stephanie, Deckert, Jurgen, del Ser, Teodoro, Denning, Nicola, Destefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Diez-Fairen, Monica, Rossi, Paolo Dionigi, Djurovic, Srdjan, Duron, Emmanuelle, Duzel, Emrah, Dufouil, Carole, Eiriksdottir, Gudny, Engelborghs, Sebastiaan, Escott-Price, Valentina, Espinosa, Ana, Ewers, Michael, Faber, Kelley M., Fabrizio, Tagliavini, Nielsen, Sune Fallgaard, Fardo, David W., Farotti, Lucia, Fenoglio, Chiara, Fernandez-Fuertes, Marta, Ferrari, Raffaele, Ferreira, Catarina B., Ferri, Evelyn, Fin, Bertrand, Fischer, Peter, Fladby, Tormod, Fliessbach, Klaus, Fongang, Bernard, Fornage, Myriam, Fortea, Juan, Foroud, Tatiana M., Fostinelli, Silvia, Fox, Nick C., Franco-Macias, Emlio, Bullido, Maria J., Frank-Garcia, Ana, Froelich, Lutz, Fulton-Howard, Brian, Galimberti, Daniela, Maria Garcia-Alberca, Jose, Garcia-Madrona, Sebastian, Garcia-Ribas, Guillermo, Ghidoni, Roberta, Giegling, Ina, Giorgio, Giaccone, Goate, Alison M., Goldhardt, Oliver, Gomez-Fonseca, Duber, Gonzalez-Perez, Antonio, Graff, Caroline, Grande, Giulia, Green, Emma, Grimmer, Timo, Grunblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Guetta-Baranes, Tamar, Haapasalo, Annakaisa, Hadjigeorgiou, Georgios, Haines, Jonathan L., Hamilton-Nelson, Kara L., Hampel, Harald, Hanon, Olivier, Hardy, John, Hartmann, Annette M., Hausner, Lucrezia, Harwood, Janet, Heilmann-Heimbach, Stefanie, Helisalmi, Seppo, Heneka, Michael T., Hernandez, Isabel, Herrmann, Martin J., Hoffmann, Per, Holmes, Clive, Holstege, Henne, Huerto Vilas, Raquel, Hulsman, Marc, Humphrey, Jack, Biessels, Geert Jan, Jian, Xueqiu, Johansson, Charlotte, Jun, Gyungah R., Kastumata, Yuriko, Kauwe, John, Kehoe, Patrick G., Kilander, Lena, Stahlbom, Anne Kinhult, Kivipelto, Miia, Koivisto, Anne, Kornhuber, Johannes, Kosmidis, Mary H., Kukull, Walter A., Kuksa, Pavel P., Kunkle, Brian W., Kuzma, Amanda B., Lage, Carmen, Laukka, Erika J., Launer, Lenore, Lauria, Alessandra, Lee, Chien-Yueh, Lehtisalo, Jenni, Lerch, Ondrej, Lleo, Alberto, Longstreth, William, Jr., Lopez, Oscar, Lopez de Munain, Adolfo, Love, Seth, Lowemark, Malin, Luckcuck, Lauren, Lunetta, Kathryn L., Ma, Yiyi, Macias, Juan, Macleod, Catherine A., Maier, Wolfgang, Mangialasche, Francesca, Spallazzi, Marco, Marquie, Marta, Marshall, Rachel, Martin, Eden R., Martin Montes, Angel, Martinez Rodriguez, Carmen, Masullo, Carlo, Mayeux, Richard, Mead, Simon, Mecocci, Patrizia, Medina, Miguel, Meggy, Alun, Mehrabian, Shima, Mendoza, Silvia, Menendez-Gonzalez, Manuel, Mir, Pablo, Moebus, Susanne, Mol, Merel, Molina-Porcel, Laura, Montrreal, Laura, Morelli, Laura, Moreno, Fermin, Morgan, Kevin, Mosley, Thomas, Nothen, Markus M., Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Borge G., Olaso, Robert, Orellana, Adelina, Orsini, Michela, Ortega, Gemma, Padovani, Alessandro, Paolo, Caffarra, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peloso, Gina, Perez-Cordon, Alba, Perez-Tur, Jordi, Pericard, Pierre, Peters, Oliver, Pijnenburg, Yolande A. L., Pineda, Juan A., Pinol-Ripoll, Gerard, Pisanu, Laudia, Polak, Thomas, Popp, Julius, Posthuma, Danielle, Priller, Josef, Puerta, Raquel, Quenez, Olivier, Quintela, Ines, Thomassen, Jesper Qvist, Rabano, Alberto, Rainero, Innocenzo, Rajabli, Farid, Ramakers, Inez, Real, Luis M., Reinders, Marcel J. T., Reitz, Christiane, Reyes-Dumeyer, Dolly, Ridge, Perry, Riedel-Heller, Steffi, Riederer, Peter, Roberto, Natalia, Rodriguez-Rodriguez, Eloy, Rongve, Arvid, Rosas Allende, Irene, Rosende-Roca, Maitee, Luis Royo, Jose, Rubino, Elisa, Rujescu, Dan, Eugenia Saez, Maria, Sakka, Paraskevi, Saltvedt, Ingvild, Bernal Sanchez-Arjona, Maria, Sanchez-Garcia, Florentino, Sanchez Juan, Pascual, Sanchez-Valle, Raquel, Sando, Sigrid B., Sarnowski, Chloe, Satizabal, Claudia L., Scamosci, Michela, Scarmeas, Nikolaos, Scarpini, Elio, Scheltens, Philip, Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias, Schneider, Anja, Schott, Jonathan M., Selbaek, Geir, Seripa, Davide, Serrano, Manuel, Sha, Jin, Shadrin, Alexey A., Skrobot, Olivia, Slifer, Susan, Snijders, Gijsje J. L., Soininen, Hilkka, Solfrizzi, Vincenzo, Solomon, Alina, Song, Yeunjoo, Sorbi, Sandro, Sotolongo-Grau, Oscar, Spalletta, Gianfranco, Spottke, Annika, Squassina, Alessio, Stordal, Eystein, Pablo Tartan, Juan, Tarraga, Lluis, Tesi, Niccolo, Thalamuthu, Anbupalam, Thomas, Tegos, Tosto, Giuseppe, Traykov, Latchezar, Tremolizzo, Lucio, Tybjaerg-Hansen, Anne, Uitterlinden, Andre, Ullgren, Abbe, Ulstein, Ingun, Valero, Sergi, Valladares, Otto, Van Broeckhoven, Christine, Vance, Jeffery, Vardarajan, Badri N., van der Lugt, Aad, Van Dongen, Jasper, van Rooij, Jeroen, van Swieten, John, Vandenberghe, Rik, Verhey, Frans, Vidal, Jean-Sebastien, Vogelgsang, Jonathan, Vyhnalek, Martin, Wagner, Michael, Wallon, David, Wang, Li-San, Wang, Ruiqi, Weinhold, Leonie, Wiltfang, Jens, Windle, Gill, Woods, Bob, Yannakoulia, Mary, Zare, Habil, Zhao, Yi, Zhang, Xiaoling, Zhu, Congcong, Zulaica, Miren, Farrer, Lindsay A., Psaty, Bruce M., Ghanbari, Mohsen, Raj, Towfique, Sachdev, Perminder, Mather, Karen, Jessen, Frank, Ikram, M. Arfan, de Mendonca, Alexandre, Hort, Jakub, Tsolaki, Magda, Pericak-Vance, Margaret A., Amouyel, Philippe, Williams, Julie, Frikke-Schmidt, Ruth, Clarimon, Jordi, Deleuze, Jean-Francois, Rossi, Giacomina, Seshadri, Sudha, Andreassen, Ole A., Ingelsson, Martin, Hiltunen, Mikko, Sleegers, Kristel, Schellenberg, Gerard D., van Duijn, Cornelia M., Sims, Rebecca, van der Flier, Wiesje M., Ruiz, Agustin, Ramirez, Alfredo, and Lambert, Jean-Charles

Abstract

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE epsilon 4 allele. Meta-analysis of genome-wide association studies on Alzheimer's disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer's disease and dementia.

Published
2022

33. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

Author

de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernandez, Isabel, Montrreal, Laura, Antunez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Celine, Quintela, Ines, Gonzalez-Perez, Antonio, Calero, Miguel, Franco-Macias, Emilio, Macias, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menendez-Gonzalez, Manuel, Frank-Garcia, Ana, Luis Royo, Jose, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Monica, Lage, Carmen, Garcia-Madrona, Sebastian, Garcia-Gonzalez, Pablo, Alarcon-Martin, Emilio, Valero, Sergi, Sotolongo-Grau, Oscar, Ullgren, Abbe, Naj, Adam C., Lemstra, Afina W., Benaque, Alba, Perez-Cordon, Alba, Benussi, Alberto, Rabano, Alberto, Padovani, Alessandro, Squassina, Alessio, de Mendonca, Alexandre, Arias Pastor, Alfonso, Kok, Almar A. L., Meggy, Alun, Belen Pastor, Ana, Espinosa, Ana, Corma-Gomez, Anais, Martin Montes, Angel, Sanabria, Angela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Stahlbom, Anne Kinhult, Tybjaerg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbaton-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Borge G., Kunkle, Brian W., Charbonnier, Camille, Abdelnour, Carla, Masullo, Carlo, Martinez Rodriguez, Carmen, Munoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Gruenblatt, Edna, Dardiotis, Efthimios, Duezel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Kucukali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gael, Selbaek, Geir, Ortega, Gemma, Chene, Genevieve, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Allende, Irene Rosas, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Juergen, Buerger, Katharina, Morgan, Kevin, Fliessbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitee, Lowenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Sanchez-Arjona, Maria Bernal, Carolina Dalmasso, Maria, Teresa Martinez-Larrad, Maria, Arcaro, Marina, Noethen, Markus M., Fernandez-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossu, Paola, Caffarra, Paolo, Rossi, Paolo Dionigi, Sakka, Paraskevi, Hoffmann, Per, Holmans, Peter A., Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N., Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hagg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Sando, Sigrid Botne, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande A. L., Smith, A. David, Abdelnour, C., Adarmes-Gomez, A. D., Macleod, C., Kehoe, Patrick Gavin, Garcia-Ribas, Guillermo, Sanchez-Juan, Pascual, Pastor, Pau, Perez-Tur, Jordi, Pinol-Ripoll, Gerard, de Munain, Adolfo Lopez, Maria Garcia-Alberca, Jose, Bullido, Maria J., Alvarez, Victoria, Lleo, Alberto, Real, Luis M., Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquie, Marta, Eugenia Saez, Maria, Carracedo, Angel, Amouyel, Philippe, Schellenberg, Gerard D., Williams, Julie, Seshadri, Sudha, van Duijn, Cornelia M., Mather, Karen A., Sanchez-Valle, Raquel, Serrano-Rios, Manuel, Orellana, Adelina, Tarraga, Lluis, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A., Posthuma, Danielle, Clarimon, Jordi, Boada, Merce, van der Flier, Wiesje M., Ramirez, Alfredo, Lambert, Jean-Charles, van der Lee, Sven J., Ruiz, Agustin, de Rojas, Itziar, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, Nancy L., Stringa, Najada, Zettergren, Anna, Hernandez, Isabel, Montrreal, Laura, Antunez, Carmen, Antonell, Anna, Tankard, Rick M., Bis, Joshua C., Sims, Rebecca, Bellenguez, Celine, Quintela, Ines, Gonzalez-Perez, Antonio, Calero, Miguel, Franco-Macias, Emilio, Macias, Juan, Blesa, Rafael, Cervera-Carles, Laura, Menendez-Gonzalez, Manuel, Frank-Garcia, Ana, Luis Royo, Jose, Moreno, Fermin, Huerto Vilas, Raquel, Baquero, Miquel, Diez-Fairen, Monica, Lage, Carmen, Garcia-Madrona, Sebastian, Garcia-Gonzalez, Pablo, Alarcon-Martin, Emilio, Valero, Sergi, Sotolongo-Grau, Oscar, Ullgren, Abbe, Naj, Adam C., Lemstra, Afina W., Benaque, Alba, Perez-Cordon, Alba, Benussi, Alberto, Rabano, Alberto, Padovani, Alessandro, Squassina, Alessio, de Mendonca, Alexandre, Arias Pastor, Alfonso, Kok, Almar A. L., Meggy, Alun, Belen Pastor, Ana, Espinosa, Ana, Corma-Gomez, Anais, Martin Montes, Angel, Sanabria, Angela, DeStefano, Anita L., Schneider, Anja, Haapasalo, Annakaisa, Stahlbom, Anne Kinhult, Tybjaerg-Hansen, Anne, Hartmann, Annette M., Spottke, Annika, Corbaton-Anchuelo, Arturo, Rongve, Arvid, Borroni, Barbara, Arosio, Beatrice, Nacmias, Benedetta, Nordestgaard, Borge G., Kunkle, Brian W., Charbonnier, Camille, Abdelnour, Carla, Masullo, Carlo, Martinez Rodriguez, Carmen, Munoz-Fernandez, Carmen, Dufouil, Carole, Graff, Caroline, Ferreira, Catarina B., Chillotti, Caterina, Reynolds, Chandra A., Fenoglio, Chiara, Van Broeckhoven, Christine, Clark, Christopher, Pisanu, Claudia, Satizabal, Claudia L., Holmes, Clive, Buiza-Rueda, Dolores, Aarsland, Dag, Rujescu, Dan, Alcolea, Daniel, Galimberti, Daniela, Wallon, David, Seripa, Davide, Gruenblatt, Edna, Dardiotis, Efthimios, Duezel, Emrah, Scarpini, Elio, Conti, Elisa, Rubino, Elisa, Gelpi, Ellen, Rodriguez-Rodriguez, Eloy, Duron, Emmanuelle, Boerwinkle, Eric, Ferri, Evelyn, Tagliavini, Fabrizio, Kucukali, Fahri, Pasquier, Florence, Sanchez-Garcia, Florentino, Mangialasche, Francesca, Jessen, Frank, Nicolas, Gael, Selbaek, Geir, Ortega, Gemma, Chene, Genevieve, Hadjigeorgiou, Georgios, Rossi, Giacomina, Spalletta, Gianfranco, Giaccone, Giorgio, Grande, Giulia, Binetti, Giuliano, Papenberg, Goran, Hampel, Harald, Bailly, Henri, Zetterberg, Henrik, Soininen, Hilkka, Karlsson, Ida K., Alvarez, Ignacio, Appollonio, Ildebrando, Giegling, Ina, Skoog, Ingmar, Saltvedt, Ingvild, Rainero, Innocenzo, Allende, Irene Rosas, Hort, Jakub, Diehl-Schmid, Janine, Van Dongen, Jasper, Vidal, Jean-Sebastien, Lehtisalo, Jenni, Wiltfang, Jens, Thomassen, Jesper Qvist, Kornhuber, Johannes, Haines, Jonathan L., Vogelgsang, Jonathan, Pineda, Juan A., Fortea, Juan, Popp, Julius, Deckert, Juergen, Buerger, Katharina, Morgan, Kevin, Fliessbach, Klaus, Sleegers, Kristel, Molina-Porcel, Laura, Kilander, Lena, Weinhold, Leonie, Farrer, Lindsay A., Wang, Li-San, Kleineidam, Luca, Farotti, Lucia, Parnetti, Lucilla, Tremolizzo, Lucio, Hausner, Lucrezia, Benussi, Luisa, Froelich, Lutz, Ikram, M. Arfan, Deniz-Naranjo, M. Candida, Tsolaki, Magda, Rosende-Roca, Maitee, Lowenmark, Malin, Hulsman, Marc, Spallazzi, Marco, Pericak-Vance, Margaret A., Esiri, Margaret, Sanchez-Arjona, Maria Bernal, Carolina Dalmasso, Maria, Teresa Martinez-Larrad, Maria, Arcaro, Marina, Noethen, Markus M., Fernandez-Fuertes, Marta, Dichgans, Martin, Ingelsson, Martin, Herrmann, Martin J., Scherer, Martin, Vyhnalek, Martin, Kosmidis, Mary H., Yannakoulia, Mary, Schmid, Matthias, Ewers, Michael, Heneka, Michael T., Wagner, Michael, Scamosci, Michela, Kivipelto, Miia, Hiltunen, Mikko, Zulaica, Miren, Alegret, Montserrat, Fornage, Myriam, Roberto, Natalia, van Schoor, Natasja M., Seidu, Nazib M., Banaj, Nerisa, Armstrong, Nicola J., Scarmeas, Nikolaos, Scherbaum, Norbert, Goldhardt, Oliver, Hanon, Oliver, Peters, Oliver, Skrobot, Olivia Anna, Quenez, Olivier, Lerch, Ondrej, Bossu, Paola, Caffarra, Paolo, Rossi, Paolo Dionigi, Sakka, Paraskevi, Hoffmann, Per, Holmans, Peter A., Fischer, Peter, Riederer, Peter, Yang, Qiong, Marshall, Rachel, Kalaria, Rajesh N., Mayeux, Richard, Vandenberghe, Rik, Cecchetti, Roberta, Ghidoni, Roberta, Frikke-Schmidt, Ruth, Sorbi, Sandro, Hagg, Sara, Engelborghs, Sebastiaan, Helisalmi, Seppo, Sando, Sigrid Botne, Kern, Silke, Archetti, Silvana, Boschi, Silvia, Fostinelli, Silvia, Gil, Silvia, Mendoza, Silvia, Mead, Simon, Ciccone, Simona, Djurovic, Srdjan, Heilmann-Heimbach, Stefanie, Riedel-Heller, Steffi, Kuulasmaa, Teemu, del Ser, Teodoro, Lebouvier, Thibaud, Polak, Thomas, Ngandu, Tiia, Grimmer, Timo, Bessi, Valentina, Escott-Price, Valentina, Giedraitis, Vilmantas, Deramecourt, Vincent, Maier, Wolfgang, Jian, Xueqiu, Pijnenburg, Yolande A. L., Smith, A. David, Abdelnour, C., Adarmes-Gomez, A. D., Macleod, C., Kehoe, Patrick Gavin, Garcia-Ribas, Guillermo, Sanchez-Juan, Pascual, Pastor, Pau, Perez-Tur, Jordi, Pinol-Ripoll, Gerard, de Munain, Adolfo Lopez, Maria Garcia-Alberca, Jose, Bullido, Maria J., Alvarez, Victoria, Lleo, Alberto, Real, Luis M., Mir, Pablo, Medina, Miguel, Scheltens, Philip, Holstege, Henne, Marquie, Marta, Eugenia Saez, Maria, Carracedo, Angel, Amouyel, Philippe, Schellenberg, Gerard D., Williams, Julie, Seshadri, Sudha, van Duijn, Cornelia M., Mather, Karen A., Sanchez-Valle, Raquel, Serrano-Rios, Manuel, Orellana, Adelina, Tarraga, Lluis, Blennow, Kaj, Huisman, Martijn, Andreassen, Ole A., Posthuma, Danielle, Clarimon, Jordi, Boada, Merce, van der Flier, Wiesje M., Ramirez, Alfredo, Lambert, Jean-Charles, van der Lee, Sven J., and Ruiz, Agustin

Abstract

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n=409,435 and validation size n=58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE 4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease. Known genetic loci account for only a fraction of the genetic contribution to Alzheimer's disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer's disease polygenic risk score.

Published
2021

34. Multiomics Profiling of Alzheimer's Disease Serum for the Identification of Autoantibody Biomarkers

Author

San Segundo-Acosta, Pablo, Montero-Calle, Ana, Jernbom-Falk, August, Alonso-Navarro, Miren, Pin, Elisa, Andersson, Eni, Hellström, Cecilia, Sanchez-Martinez, Maricruz, Rabano, Alberto, Solis-Fernandez, Guillermo, Pelaez-Garcia, Alberto, Martinez-Useros, Javier, Fernandez-Acenero, Maria Jesus, Månberg, Anna, Nilsson, Peter, Barderas, Rodrigo, San Segundo-Acosta, Pablo, Montero-Calle, Ana, Jernbom-Falk, August, Alonso-Navarro, Miren, Pin, Elisa, Andersson, Eni, Hellström, Cecilia, Sanchez-Martinez, Maricruz, Rabano, Alberto, Solis-Fernandez, Guillermo, Pelaez-Garcia, Alberto, Martinez-Useros, Javier, Fernandez-Acenero, Maria Jesus, Månberg, Anna, Nilsson, Peter, and Barderas, Rodrigo

Abstract

New biomarkers of Alzheimer's disease (AD) with a diagnostic value in preclinical and prodromal stages are urgently needed. AD-related serum autoantibodies are potential candidate biomarkers. Here, we aimed at identifying AD-related serum autoantibodies using protein microarrays and mass spectrometry-based methods. To this end, an untargeted complementary screening using high-density (42,100 antigens) and low-density (384 antigens) planar protein-epitope signature tag (PrEST) arrays and an immunoprecipitation protocol coupled to mass spectrometry analysis were used for serum autoantibody profiling. From the untargeted screening phase, 377 antigens corresponding to 338 proteins were selected for validation. Out of them, IVD, CYFIP1, and ADD2 seroreactivity was validated using 128 sera from AD patients and controls by PrEST-suspension bead arrays, and ELISA or luminescence Halotag-based bead immunoassay using full-length recombinant proteins. Importantly, IVD, CYFIP1, and ADD2 showed in combination a noticeable AD diagnostic ability. Moreover, IVD protein abundance in the prefrontal cortex was significantly two-fold higher in AD patients than in controls by western blot and immunohistochemistry, whereas CYFIP1 and ADD2 were significantly down-regulated in AD patients. The panel of AD-related autoantigens identified by a comprehensive multiomics approach may provide new insights of the disease and should help in the blood-based diagnosis of Alzheimer's disease. Mass spectrometry raw data are available in the ProteomeXchange database with the access number PXD028392., QC 20211201

Published
2021
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37. Effect of the micro-environment on alpha-synuclein conversion and implication in seeded conversion assays

Author

Candelise, Niccolo, Schmitz, Matthias, Thüne, Katrin, Cramm, Maria, Rabano, Alberto, Zafar, Saima, Stoops, Erik, Vanderstichele, Hugo, Villar Piqué, Anna, Llorens Torres, Franc, and Zerr, Inga

Subjects
Alpha-synuclein, nervous system, animal diseases, Malaltia de Parkinson, Parkinson's disease, mental disorders, Demència amb cossos de Lewy, Alfa-sinucleïna, Lewy body dementia, nervous system diseases
Abstract

Background: α-Synuclein is a small soluble protein, whose physiological function in the healthy brain is poorly understood. Intracellular inclusions of α-synuclein, referred to as Lewy bodies (LBs), are pathological hallmarks of α- synucleinopathies, such as Parkinson’s disease (PD) or dementia with Lewy bodies (DLB). Main body: Understanding of the molecular basis as well as the factors or conditions promoting α-synuclein misfolding and aggregation is an important step towards the comprehension of pathological mechanism of α- synucleinopathies and for the development of efficient therapeutic strategies. Based on the conversion and aggregation mechanism of α-synuclein, novel diagnostic tests, such as protein misfolding seeded conversion assays, e.g. the real-time quaking-induced conversion (RT-QuIC), had been developed. In diagnostics, α-synuclein RT-QuIC exhibits a specificity between 82 and 100% while the sensitivity varies between 70 and 100% among different laboratories. In addition, the α-synuclein RT-QuIC can be used to study the α-synuclein-seeding-characteristics of different α-synucleinopathies and to differentiate between DLB and PD. Conclusion: The variable diagnostic accuracy of current α-synuclein RT-QuIC occurs due to different protocols, cohorts and material etc.. An impact of micro-environmental factors on the α-synuclein aggregation and conversion process and the occurrence and detection of differential misfolded α-synuclein types or strains might underpin the clinical heterogeneity of α-synucleinopathies.

Published
2020

39. Localization and protein levels of YKL‐40 in postmortem brain of frontotemporal dementia and Alzheimer’s disease cases

Author

Hok‐A‐Hin, Yanaika S., primary, Hu, William T., additional, Wouters, Dorine, additional, Boonkamp, Lynn, additional, Howell, J. Christina, additional, Rabano, Alberto, additional, Pijnenburg, Yolande A.L., additional, Teunissen, Charlotte E., additional, Hoozemans, Jeroen J.M., additional, and Del Campo, Marta, additional

Published
2020
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44. Elevated Plasma microRNA-206 Levels Predict Cognitive Decline and Progression to Dementia from Mild Cognitive Impairment

Author

Kenny, Aidan, primary, McArdle, Hazel, additional, Calero, Miguel, additional, Rabano, Alberto, additional, Madden, Stephen, additional, Adamson, Kellie, additional, Forster, Robert, additional, Spain, Elaine, additional, Prehn, Jochen, additional, Henshall, David, additional, Medina, Miguel, additional, Jimenez-Mateos, Eva, additional, and Engel, Tobias, additional

Published
2019
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45. Seeding variability of different alpha synuclein strains in synucleinopathies

Author

Candelise, Niccolò, primary, Schmitz, Matthias, additional, Llorens, Franc, additional, Villar‐Piqué, Anna, additional, Cramm, Maria, additional, Thom, Tobias, additional, Silva Correia, Susana Margarida, additional, Cunha, José Eriton Gomes, additional, Möbius, Wiebke, additional, Outeiro, Tiago F., additional, Álvarez, Valentina González, additional, Banchelli, Martina, additional, D'Andrea, Cristiano, additional, Angelis, Marella, additional, Zafar, Saima, additional, Rabano, Alberto, additional, Matteini, Paolo, additional, and Zerr, Inga, additional

Published
2019
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46. Effects of fibroblast growth factor and glial-derived neurotrophic factor on akinesia, F-DOPA uptake and dopamine cells in parkinsonian primates

Author

Fontan, Aurora, Rojo, Ana, Sanchez Pernaute, Rosario, Hernández, Isabel, López, Isabel, Castilla, Carlos, Sanchez Albisua, Julio, Perez Higueras, Antonio, Al-Rashid, Imad, Rabano, Alberto, Gonzalo, Isabel, Angeles Mena, Maria, Cools, Alex, Eshuis, Silvia, Maguire, Paul, Pruim, Jan, Leenders, Klaus, and Garcia de Yebenes, Justo

Published
2002
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48. Tau-positive nuclear indentations in P301S tauopathy mice

Author

Fernández-Nogales, Marta, Santos-Galindo, María, Merchán-Rubira, Jesús, Hoozemans, Jeroen J. M., Rabano, Alberto, Ferrer, Isidro, Ávila, Jesús, Hernández, Félix, Lucas, José Javier, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Ministerio de Economía y Competitividad (España), Fundación BBVA, La Caixa, Universitat de Barcelona, Instituto de Salud Carlos III, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Pathology

Subjects
TNI (tau-immunopositive nuclear indentation), Tau nuclear rod, Ratolins (Animals de laboratori), Patologia, Cell nuclei, Metabolisme, Tauopathy, Metabolism, Mice (Laboratory animals), mental disorders, Pathology, Nuclis cel·lulars, Tau, TNR (tau nuclear rod), Tau, Tau-immunopositive nuclear indentation, Nuclear indentations
Abstract

Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term “tau nuclear rods (TNRs).” Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations., Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de salud Carlos III) collaborative grant PI2013/09-2, CoEN grant (NEURO-MIR) and by grants from Spanish Ministery of Economy and Competitiveness (MINECO, SAF2012-34177 and SAF2015-65371-R), Fundación BBVA and Fundación Ramón Areces.

Published
2017
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50. Identification of prefrontal cortex protein alterations in Alzheimer’s disease

Author

Garranzo-Asensio, Maria, primary, San Segundo-Acosta, Pablo, additional, Martínez-Useros, Javier, additional, Montero-Calle, Ana, additional, Fernández-Aceñero, María Jesús, additional, Häggmark-Månberg, Anna, additional, Pelaez-Garcia, Alberto, additional, Villalba, Mayte, additional, Rabano, Alberto, additional, Nilsson, Peter, additional, and Barderas, Rodrigo, additional

Published
2018
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