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https://www.readbyqxmd.com/read/28537274/characterization-of-pathogenic-sorl1-genetic-variants-for-association-with-alzheimer-s-disease-a-clinical-interpretation-strategy
#1
Henne Holstege, Sven J van der Lee, Marc Hulsman, Tsz Hang Wong, Jeroen Gj van Rooij, Marjan Weiss, Eva Louwersheimer, Frank J Wolters, Najaf Amin, André G Uitterlinden, Albert Hofman, M Arfan Ikram, John C van Swieten, Hanne Meijers-Heijboer, Wiesje M van der Flier, Marcel Jt Reinders, Cornelia M van Duijn, Philip Scheltens
Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign...
May 24, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28532646/the-novel-psen1-m84v-mutation-associated-to-frontal-dysexecutive-syndrome-spastic-paraparesis-and-cerebellar-atrophy-in-a-dominant-alzheimer-s-disease-family
#2
Maura Gallo, Francesca Frangipane, Chiara Cupidi, Matteo De Bartolo, Sabina Turone, Camilla Ferrari, Benedetta Nacmias, Giuliana Grimaldi, Valentina Laganà, Rosanna Colao, Livia Bernardi, Maria Anfossi, Maria Elena Conidi, Franca Vasso, Sabrina Anna Maria Curcio, Maria Mirabelli, Nicoletta Smirne, Giusi Torchia, Maria Gabriella Muraca, Gianfranco Puccio, Raffaele Di Lorenzo, Maristella Piccininni, Andrea Tedde, Raffaele Giovanni Maletta, Sandro Sorbi, Amalia Cecilia Bruni
We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene...
April 27, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28532645/identification-of-a-novel-psen1-mutation-leu232pro-in-a-korean-patient-with-early-onset-alzheimer-s-disease-and-a-family-history-of-dementia
#3
Jiyun Park, Seong Soo A An, Vo Van Giau, Kyuhwan Shim, Young Chul Youn, Eva Bagyinszky, SangYun Kim
In the present study, a novel mutation in exon 7 of presenilin 1 (Leu232Pro) was discovered in a Korean patient with early-onset Alzheimer's disease, who represented memory decline at 37 years of age, followed by impairment in spatial activity and concentrations and personality changes. Imaging analyses with magnetic resonance scan showed diffuse atrophy in the frontoparietal regions. Targeted next generation sequencing and Sanger sequencing identified a heterozygous T to C transition at position 695 (c.695T>C) of in presenilin 1 gene (PSEN1), resulting in a novel missense mutation at codon 232 from leucine to proline (L232P)...
April 26, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28523554/alzheimer-s-disease-and-histone-code-alterations
#4
Pritika Narayan, Mike Dragunow
Substantial progress has been made in identifying Alzheimer's disease (AD) risk-associated variants using genome-wide association studies (GWAS). The majority of these risk variants reside in noncoding regions of the genome making their functional evaluation difficult; however, they also infer the presence of unconventional regulatory regions that may reside at these locations. We know from these studies that rare familial cases of AD account for less than 5% of all AD cases and autosomal dominant mutations in APP, PSEN1 and PSEN2 account for less than 10% of the genetic basis of these familial cases [1]...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28505974/state-of-play-in-alzheimer-s-disease-genetics
#5
Jin-Bao Zhu, Chen-Chen Tan, Lan Tan, Jin-Tai Yu
Alzheimer's disease (AD), the main form of dementia in the elderly, is the most common progressive neurodegenerative disease characterized by rapidly progressive cognitive dysfunction and behavior impairment. AD exhibits a considerable heritability and great advances have been made in approaches to searching the genetic etiology of AD. In AD genetic studies, methods have developed from classic linkage-based and candidate-gene-based association studies to genome-wide association studies (GWAS) and next generation sequencing...
May 11, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28461250/deletion-of-exons-9-and-10-of-the-presenilin-1-gene-in-a-patient-with-early-onset-alzheimer-disease-generates-longer-amyloid-seeds
#6
Kilan Le Guennec, Sarah Veugelen, Olivier Quenez, Maria Szaruga, Stéphane Rousseau, Gaël Nicolas, David Wallon, Frédérique Fluchere, Thierry Frébourg, Bart De Strooper, Dominique Campion, Lucía Chávez-Gutiérrez, Anne Rovelet-Lecrux
Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56years...
April 28, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28460142/comparative-proteomics-reveals-silver-nanoparticles-alter-fatty-acid-metabolism-and-amyloid-beta-clearance-for-neuronal-apoptosis-in-a-triple-cell-co-culture-model-of-the-blood-brain-barrier
#7
Ho-Chen Lin, Ming-Yi Ho, Chao-Ming Tsen, Chien-Chu Huang, Chin-Ching Wu, Yuh-Jeen Huang, I-Lun Hsiao, Chun-Yu Chuang
Silver nanoparticles (AgNPs) enter the central nervous system through the blood-brain barrier (BBB). AgNP exposure can increase amyloid beta (Aβ) deposition in neuronal cells to potentially induce Alzheimer disease (AD) progression. However, the mechanism through which AgNPs alter BBB permeability in endothelial cells and subsequently lead to AD progression remains unclear. This study investigated whether AgNPs disrupt the tight junction proteins of brain endothelial cells, and alter the proteomic metabolism of neuronal cells underlying AD progression in a triple cell co-culture model constructed using mouse brain endothelial (bEnd...
April 29, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28448946/oral-administration-of-methysticin-improves-cognitive-deficits-in-a-mouse-model-of-alzheimer-s-disease
#8
Athanassios Fragoulis, Stephanie Siegl, Markus Fendt, Sandra Jansen, Ulf Soppa, Lars-Ove Brandenburg, Thomas Pufe, Joachim Weis, Christoph Jan Wruck
INTRODUCTION: There is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an anti-inflammatory transcription factor that regulates the oxidative stress defense. Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ)-induced oxidative stress in vitro by Nrf2 pathway activation. Here, we tested an in vivo kavalactone treatment in a mouse model of AD...
April 19, 2017: Redox Biology
https://www.readbyqxmd.com/read/28416393/tdp-43-expression-influences-amyloid%C3%AE-plaque-deposition-and-tau-aggregation
#9
Stephani A Davis, Kok Ann Gan, James A Dowell, Nigel J Cairns, Michael A Gitcho
Although the main focus in Alzheimer's disease (AD) has been an investigation of mechanisms causing Aβ plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9)...
April 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28350801/app-psen1-and-psen2-mutations-in-early-onset-alzheimer-disease-a-genetic-screening-study-of-familial-and-sporadic-cases
#10
Hélène-Marie Lanoiselée, Gaël Nicolas, David Wallon, Anne Rovelet-Lecrux, Morgane Lacour, Stéphane Rousseau, Anne-Claire Richard, Florence Pasquier, Adeline Rollin-Sillaire, Olivier Martinaud, Muriel Quillard-Muraine, Vincent de la Sayette, Claire Boutoleau-Bretonniere, Frédérique Etcharry-Bouyx, Valérie Chauviré, Marie Sarazin, Isabelle le Ber, Stéphane Epelbaum, Thérèse Jonveaux, Olivier Rouaud, Mathieu Ceccaldi, Olivier Félician, Olivier Godefroy, Maite Formaglio, Bernard Croisile, Sophie Auriacombe, Ludivine Chamard, Jean-Louis Vincent, Mathilde Sauvée, Cecilia Marelli-Tosi, Audrey Gabelle, Canan Ozsancak, Jérémie Pariente, Claire Paquet, Didier Hannequin, Dominique Campion
BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170...
March 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28304309/mouse-models-of-alzheimer-s-disease
#11
Gisela Esquerda-Canals, Laia Montoliu-Gaya, Jofre Güell-Bosch, Sandra Villegas
Alzheimer's disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28269784/a-novel-psen1-k311r-mutation-discovered-in-chinese-families-with-late-onset-alzheimer-s-disease-affects-amyloid-%C3%AE-production-and-tau-phosphorylation
#12
Jing Dong, Wei Qin, Cuibai Wei, Yi Tang, Qi Wang, Jianping Jia
BACKGROUND: Presenilin-1 (PSEN1) is the most frequently mutated gene in familial Alzheimer's disease (AD), whereas only several novel mutations have been reported in China and functional studies were seldom conducted. OBJECTIVE: We describe a novel PSEN1 K311R mutation in two Chinese families with late-onset AD and its functional impact on amyloid-β protein precursor (AβPP) processing and tau phosphorylation. METHODS: The mutation was detected by direct sequencing of PSEN1 exon 9...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28243073/a-case-of-possibly-pathogenic-psen2-r62c-mutation-in-a-patient-with-probable-early-onset-alzheimer-s-dementia-supported-by-structure-prediction
#13
Kyung Won Park, Seong Soo An, Eva Bagyinszky, SangYun Kim
A 49-year-old Korean male patient with dementia was diagnosed with probable early-onset Alzheimer's disease (AD). He presented with memory problems, personality changes, and disorientation. His family history of dementia was probably negative, since no family member with dementia was found or mentioned. Mild cortical atrophy was observed upon magnetic resonance imaging analyses of his brain, and the single-photon emission computed tomography analysis revealed hypoperfusion in the frontal, temporal, and limbic lobes...
2017: Clinical Interventions in Aging
https://www.readbyqxmd.com/read/28209190/the-effects-of-different-familial-alzheimer-s-disease-mutations-on-app-processing-in-vivo
#14
Steinunn Thordardottir, Anne Kinhult Ståhlbom, Ove Almkvist, Håkan Thonberg, Maria Eriksdotter, Henrik Zetterberg, Kaj Blennow, Caroline Graff
BACKGROUND: Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer's disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective. METHODS: In the current cross-sectional study, products of APP processing (e...
February 16, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28131463/very-early-onset-sporadic-alzheimer-s-disease-with-a-de-novo-mutation-in-the-psen1-gene
#15
Fan Lou, Xiaoguang Luo, Ming Li, Yan Ren, Zhiyi He
We report a 22-year onset age man diagnosed with rapidly progressing early-onset Alzheimer's disease with predominant extrapyramidal symptoms as the initial presenting symptoms and V391G mutation in presenilin 1 gene (PSEN1) was founded. The unaffected parents of the proband are not carriers of the mutation but have histories of extrapyramidal diseases, suggesting de novo origin of V391G mutation. The Val391Gly variation widens the number of PSEN1 mutations responsible for early-onset Alzheimer's disease with extrapyramidal phenotype and would help to establish a functional map of presenilin 1 protein architecture...
May 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28108292/reversal-of-high-fat-diet-induced-obesity-improves-glucose-tolerance-inflammatory-response-%C3%AE-amyloid-accumulation-and-cognitive-decline-in-the-app-psen1-mouse-model-of-alzheimer-s-disease
#16
Jennifer M Walker, Shilpy Dixit, Anjelica C Saulsberry, James M May, Fiona E Harrison
This study assessed the extent to which high fat diet (HFD)-induced β-amyloid accumulation and cognitive decline in APP/PSEN1 mice are reversible through control of fat intake. Ten months of HFD (60% calories from fat) led to significant deficits in a 2-trial Y maze task, and nest building assay, and decreased voluntary locomotor activity. The HFD induced an inflammatory response, indicated by increased expression of several inflammatory markers. Substituting a low fat diet led to pronounced weight loss and correction of glucose intolerance, decreases in the inflammatory response, and improved performance on behavioral tasks in both wild-type and APP/PSEN1 transgenic mice...
April 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28106563/comprehensive-screening-for-disease-risk-variants-in-early-onset-alzheimer-s-disease-genes-in-african-americans-identifies-novel-psen-variants
#17
Aurelie N'Songo, Minerva M Carrasquillo, Xue Wang, Thuy Nguyen, Yan Asmann, Steven G Younkin, Mariet Allen, Ranjan Duara, Maria T Greig Custo, Neill Graff-Radford, Nilüfer Ertekin-Taner
We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer's disease (EOAD) genes (APP, PSEN1, and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2:NM_000447:exon5:c...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28103467/-investigation-of-genetic-etiology-in-neurodegenerative-dementias-recommendations-from-the-centro-hospitalar-s%C3%A3-o-jo%C3%A3-o-neurogenetics-group
#18
João Massano, Miguel Leão, Carolina Garrett
In the past few years several gene mutations have been identified as causative of the most frequent neurodegenerative dementias (Alzheimer disease and frontotemporal dementia). These advances, along with the complex phenotype-genotype relationships and the costs associated with genetic testing, have often made it difficult for clinicians to decide with regard to a rational plan for the investigation of the genetic etiology of the degenerative dementias. The Centro Hospitalar São João Neurogenetics Group, a multidisciplinary team of Neurologists and Geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic etiology of Alzheimer disease and frontotemporal dementia in clinical practice, based on international consensus documents (currently containing partly outdated information) and published scientific evidence on this topic...
October 2016: Acta Médica Portuguesa
https://www.readbyqxmd.com/read/28079014/predicting-cognitive-decline-across-four-decades-in-mutation-carriers-and-non-carriers-in-autosomal-dominant-alzheimer-s-disease
#19
Ove Almkvist, Elena Rodriguez-Vieitez, Steinunn Thordardottir, Kaarina Amberla, Karin Axelman, Hans Basun, Anne Kinhult-Ståhlbom, Lena Lilius, Anne Remes, Lars-Olof Wahlund, Matti Viitanen, Lars Lannfelt, Caroline Graff
OBJECTIVES: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. METHODS: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers...
January 12, 2017: Journal of the International Neuropsychological Society: JINS
https://www.readbyqxmd.com/read/28075048/the-sti-and-uba-domains-of-ubqln1-are-critical-determinants-of-substrate-interaction-and-proteostasis
#20
Zimple Kurlawala, Parag P Shah, Charmi Shah, Levi J Beverly
There are five Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have three functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA), and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders ranging from Alzheimer's disease to cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control...
January 11, 2017: Journal of Cellular Biochemistry
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