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https://www.readbyqxmd.com/read/28209190/the-effects-of-different-familial-alzheimer-s-disease-mutations-on-app-processing-in-vivo
#1
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
#2
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...
January 6, 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
#3
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...
January 17, 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
#4
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...
January 19, 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
#5
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
#6
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
#7
Zimple Kurlawala, Parag P Shah, Charmi Shah, Levi J Beverly
There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 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. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation...
January 11, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28034781/increased-susceptibility-to-a%C3%AE-toxicity-in-neuronal-cultures-derived-from-familial-alzheimer-s-disease-psen1-a246e-induced-pluripotent-stem-cells
#8
Enrique Armijo, Cesar Gonzalez, Mohammad Shahnawaz, Andrea Flores, Brian Davis, Claudio Soto
Alzheimer's disease (AD) is the most common cause of late-life dementia and represents one of the leading causes of death worldwide. The generation of induced pluripotent stem cells (iPSC) has facilitated the production and differentiation of stem cells from patients somatic cells, offering new opportunities to model AD and other diseases in vitro. In this study, we generated iPSCs from skin fibroblasts obtained from a healthy individual, as well as sporadic (sAD) and familial AD (fAD, PSEN1-A246E mutation) patients...
February 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28008242/a-genetic-screen-of-the-mutations-in-the-korean-patients-with-early-onset-alzheimer-s-disease
#9
Seong Soo An, Sun Ah Park, Eva Bagyinszky, Sun Oh Bae, Yoon-Jeong Kim, Ji Young Im, Kyung Won Park, Kee Hyung Park, Eun-Joo Kim, Jee Hyang Jeong, Jong Hun Kim, Hyun Jeong Han, Seong Hye Choi, SangYun Kim
Early-onset Alzheimer's disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer's disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study...
2016: Clinical Interventions in Aging
https://www.readbyqxmd.com/read/28002825/from-common-to-rare-variants-the-genetic-component-of-alzheimer-disease
#10
Gaël Nicolas, Camille Charbonnier, Dominique Campion
Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player...
2016: Human Heredity
https://www.readbyqxmd.com/read/27926491/early-pathogenic-event-of-alzheimer-s-disease-documented-in-ipscs-from-patients-with-psen1-mutations
#11
Juan Yang, Hanzhi Zhao, Yu Ma, Guilai Shi, Jian Song, Yu Tang, Song Li, Ting Li, Nan Liu, Fan Tang, Junjie Gu, Lingling Zhang, Zhuohua Zhang, Xiaohui Zhang, Ying Jin, Weidong Le
Alzheimer's disease (AD) is the most common age-related dementia characterized by progressive neuronal loss. However, the molecular mechanisms for the neuronal loss is still debated. Here, we used induced pluripotent stem cells (iPSCs) derived from somatic cells of familial AD patients carrying PSEN1 mutations to study the early pathogenic event of AD. We found that premature neuronal differentiation with decreased proliferation and increased apoptosis occured in AD-iPSC-derived neural progenitor cells (AD-NPCs) once neuronal differentiation was initiated, together with higher levels of Aβ42 and phosphorylated tau...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/27911290/rare-genetic-variant-in-sorl1-may-increase-penetrance-of-alzheimer-s-disease-in-a-family-with-several-generations-of-apoe-%C3%A9-4-homozygosity
#12
Eva Louwersheimer, Petra E Cohn-Hokke, Yolande A L Pijnenburg, Marjan M Weiss, Erik A Sistermans, Annemieke J Rozemuller, Marc Hulsman, John C van Swieten, Cock M van Duijn, Frederik Barkhof, Teddy Koene, Philip Scheltens, Wiesje M Van der Flier, Henne Holstege
BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD. METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27900998/novel-mutations-in-psenen-gene-in-two-chinese-acne-inversa-families-manifested-as-familial-multiple-comedones-and-dowling-degos-disease
#13
Cheng Zhou, Guang-Dong Wen, Lwin Myint Soe, Hong-Jun Xu, Juan Du, Jian-Zhong Zhang
BACKGROUND: Acne inversa (AI), also called hidradenitis suppurativa, is a chronic, inflammatory, recurrent skin disease of the hair follicle. Familial AI shows autosomal-dominant inheritance caused by mutations in the γ-secretase genes. This study was aimed to identify the specific mutations in the γ-secretase genes in two Chinese families with AI. METHODS: In this study, two Chinese families with AI were investigated. All the affected individuals in the two families mainly manifested with multiple comedones, pitted scars, and a few inflammatory nodules on their face, neck, trunk, axilla, buttocks, upper arms, and thighs...
2016: Chinese Medical Journal
https://www.readbyqxmd.com/read/27897204/human-mitochondrial-transcriptional-factor-a-breaks-the-mitochondria-mediated-vicious-cycle-in-alzheimer-s-disease
#14
Sugako Oka, Julio Leon, Kunihiko Sakumi, Tomomi Ide, Dongchon Kang, Frank M LaFerla, Yusaku Nakabeppu
In the mitochondria-mediated vicious cycle of Alzheimer's disease (AD), intracellular amyloid β (Aβ) induces mitochondrial dysfunction and reactive oxygen species, which further accelerate Aβ accumulation. This vicious cycle is thought to play a pivotal role in the development of AD, although the molecular mechanism remains unclear. Here, we examined the effects of human mitochondrial transcriptional factor A (hTFAM) on the pathology of a mouse model of AD (3xTg-AD), because TFAM is known to protect mitochondria from oxidative stress through maintenance of mitochondrial DNA (mtDNA)...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27888801/common-profiles-of-notch-signaling-differentiate-disease-free-survival-in-luminal-type-a-and-triple-negative-breast-cancer
#15
Magdalena Orzechowska, Dorota Jędroszka, Andrzej K Bednarek
Breast cancer (BC) is characterized by high heterogeneity regarding its biology and clinical characteristics. The Notch pathway regulates such processes as organ modeling and epithelial-to-mesenchymal transition (EMT).The aim of the study was to determine the effect of differential expression of Notch members on disease-free survival (DFS) in luminal type A (lumA) and triple negative (TN) BC.The differential expression of 19 Notch members was examined in a TCGA BC cohort. DFS analysis was performed using the log-rank test (p<0...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/27883225/computational-screening-and-exploration-of-disease-associated-genes-in-alzheimer-s-disease
#16
Salma Jamal, Sukriti Goyal, Asheesh Shanker, Abhinav Grover
Alzheimer's is a neurodegenerative disease affecting large populations worldwide characterized mainly by progressive loss of memory along with various other symptoms. The foremost cause of the disease is still unclear, however various mechanisms have been proposed to cause the disease that include amyloid hypothesis, tau hypothesis, and cholinergic hypothesis in addition to genetic factors. Various genes have been known to be involved which are APOE, PSEN1, PSEN2, and APP among others. In the present study, we have used computational methods to examine the pathogenic effects of non-synonymous single nucleotide polymorphisms (SNPs) associated with ABCA7, CR1, MS4A6A, CD2AP, PSEN1, PSEN2, and APP genes...
November 24, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27879212/generation-of-a-gene-corrected-isogenic-control-cell-line-from-an-alzheimer-s-disease-patient-ipsc-line-carrying-a-a79v-mutation-in-psen1
#17
Carlota Pires, Benjamin Schmid, Carina Petræus, Anna Poon, Natakarn Nimsanor, Troels T Nielsen, Gunhild Waldemar, Lena E Hjermind, Jørgen E Nielsen, Poul Hyttel, Kristine K Freude
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease causing neural cell degeneration and brain atrophy and is considered to be the most common form of dementia. We previously generated an induced pluripotent stem cell (iPSC) line from an AD patient carrying an A79V mutation in PSEN1 as an in vitro disease model. Here we generated a gene-corrected version from this hiPSC line by substituting the point mutation with the wild-type sequence. The reported A79V-GC-iPSCs line is a very useful resource in combination with the A79V-iPSC line in order to study pathological cellular phenotypes related to this particular mutation...
September 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27858713/protein-expression-of-bace1-is-downregulated-by-donepezil-in-alzheimer-s-disease-platelets
#18
Tamires Alves Sarno, Leda Leme Talib, Helena Passarelli Giroud Joaquim, Jessyka Maria de França Bram, Wagner Farid Gattaz, Orestes Vicente Forlenza
BACKGROUND: Abnormal amyloid-β protein precursor (AβPP) metabolism is a key feature of Alzheimer's disease (AD). Platelets contain most of the enzymatic machinery required for AβPP processing, and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. Thus, AβPP-related molecules in platelets may be regarded as peripheral markers of AD. OBJECTIVE: We sought to determine the protein expression of the AβPP secretases (ADAM10, BACE1, and PSEN1) and AβPP ratio in platelets of patients with mild or moderate AD compared to healthy controls...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27836335/a-novel-presenilin-1-mutation-f388l-identified-in-a-chinese-family-with-early-onset-alzheimer-s-disease
#19
Yihong Zhan, Honghua Zheng, Chen Wang, Zhouyi Rong, Naian Xiao, Qilin Ma, Yun-Wu Zhang
A subset of Alzheimer's disease (AD) occurrence shows autosomal dominant, familial inheritance patterns. Such familial AD (FAD) are caused by mutations in APP, PSEN1, and PSEN2 genes, which encode amyloid-β (Aβ) precursor protein, presenilin 1 (PS1), and presenilin 2 (PS2), respectively. Here, we report a novel PSEN1 mutation (c.1164C > G, p.F388L, mutation nomenclature according to National Center for Biotechnology Information Reference Sequence: NM_000021.3) occurring in a Chinese family with early-onset AD and cosegregating with affected family members...
February 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/27816212/novel-presenilin-1-mutation-p-f386i-in-a-chinese-family-with-early-onset-alzheimer-s-disease
#20
Yat-Fung Shea, Angel On-Kei Chan, Leung-Wing Chu, Shui-Ching Lee, Chun-Yin Law, Chung-Him See, Kit-Ling Yiu, Patrick Ka-Chun Chiu
Autosomal dominant familial Alzheimer's disease accounts for 0.5% of all Alzheimer's disease. A familial Alzheimer's disease Chinese family, with 7 affected family members, underwent PSEN1 screening in 3 affected family members. A heterozygous novel missense mutation in the PSEN1 gene c.1156T>A, altering phenylalanine to isoleucine at codon 386, was identified. Because the change occurred in conserved domains of this gene and cosegregated with affected family members, this change may have a mutagenic and probably pathogenic effect...
February 2017: Neurobiology of Aging
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