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https://www.readbyqxmd.com/read/29137240/mutational-re-modeling-of-di-aspartyl-intramembrane-proteases-uncoupling-physiologically-relevant-activities-from-those-associated-with-alzheimer-s-disease
#1
Anastasia P Grigorenko, Youri K Moliaka, Olga V Plotnikova, Alexander Smirnov, Vera A Nikishina, Andrey Y Goltsov, Fedor Gusev, Tatiana V Andreeva, Omar Nelson, Ilya Bezprozvanny, Evgeny I Rogaev
The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of β-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aβ, but not the ε-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29105065/reduced-blood-brain-barrier-expression-of-fatty-acid-binding-protein-5-is-associated-with-increased-vulnerability-of-app-ps1-mice-to-cognitive-deficits-from-low-omega-3-fatty-acid-diets
#2
Yijun Pan, Kwok H C Choy, Philip J Marriott, Siew Y Chai, Martin J Scanlon, Christopher J H Porter, Jennifer L Short, Joseph A Nicolazzo
Lower levels of the cognitively-beneficial docosahexaenoic acid (DHA) are often observed in Alzheimer's disease (AD) brains. Brain DHA levels are regulated by the blood-brain barrier (BBB) transport of plasma-derived DHA, a process facilitated by fatty acid-binding protein 5 (FABP5). This study reports a 42.1 ± 12.6% decrease in the BBB transport of (14) C-DHA in 8-month AD transgenic mice (APPswe,PSEN1∆E9) relative to wild-type, associated with a 34.5 ± 6.7% reduction in FABP5 expression in isolated brain capillaries of AD mice...
November 3, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29103038/complexity-and-selectivity-of-%C3%AE-secretase-cleavage-on-multiple-substrates-consequences-in-alzheimer-s-disease-and-cancer
#3
Alessandro Medoro, Silvia Bartollino, Donatella Mignogna, Daniela Passarella, Carola Porcile, Aldo Pagano, Tullio Florio, Mario Nizzari, Germano Guerra, Roberto Di Marco, Mariano Intrieri, Gennaro Raimo, Claudio Russo
The processing of the amyloid-β protein precursor (AβPP) by β- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AβPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration...
November 1, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29091718/analysis-of-neurodegenerative-mendelian-genes-in-clinically-diagnosed-alzheimer-disease
#4
Maria Victoria Fernández, Jong Hun Kim, John P Budde, Kathleen Black, Alexandra Medvedeva, Ben Saef, Yuetiva Deming, Jorge Del-Aguila, Laura Ibañez, Umber Dube, Oscar Harari, Joanne Norton, Rachel Chasse, John C Morris, Alison Goate, Carlos Cruchaga
Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America...
November 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29081698/population-based-study-of-risk-polymorphisms-associated-with-vascular-disorders-and-dementia
#5
Óscar Teijido, Juan Carlos Carril, Ramón Cacabelos
INTRODUCTION: Cardiovascular and neurodegenerative disorders are among the major causes of mortality in the developed countries. Population studies evaluate the genetic risk, i.e. the probability of an individual carrying a specific disease-associated polymorphism. Identification of risk polymorphisms is essential for an accurate diagnosis or prognosis of a number of pathologies. AIMS: The aim of this study was to characterize the influence of risk polymorphisms associated with lipid metabolism, hypertension, thrombosis, and dementia, in a large population of Spanish individuals affected by a variety of brain and vascular disorders as well as metabolic syndrome...
October 2017: Current Genomics
https://www.readbyqxmd.com/read/29078389/dominant-negative-effect-of-the-loss-of-function-%C3%AE-secretase-mutants-on-the-wild-type-enzyme-through-heterooligomerization
#6
Rui Zhou, Guanghui Yang, Yigong Shi
γ-secretase is an intramembrane protease complex consisting of nicastrin, presenilin-1/2, APH-1a/b, and Pen-2. Hydrolysis of the 99-residue transmembrane fragment of amyloid precursor protein (APP-C99) by γ-secretase produces β-amyloid (Aβ) peptides. Pathogenic mutations in PSEN1 and PSEN2, which encode the catalytic subunit presenilin-1/2 of γ-secretase, lead to familial Alzheimer's disease in an autosomal dominant manner. However, the underlying mechanism of how the mutant PSEN gene may affect the function of the WT allele remains to be elucidated...
October 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29070659/serum-neurofilament-light-in-familial-alzheimer-disease-a-marker-of-early-neurodegeneration
#7
Philip S J Weston, Teresa Poole, Natalie S Ryan, Akshay Nair, Yuying Liang, Kirsty Macpherson, Ronald Druyeh, Ian B Malone, R Laila Ahsan, Hugh Pemberton, Jana Klimova, Simon Mead, Kaj Blennow, Martin N Rossor, Jonathan M Schott, Henrik Zetterberg, Nick C Fox
OBJECTIVES: To investigate whether serum neurofilament light (NfL) concentration is increased in familial Alzheimer disease (FAD), both pre and post symptom onset, and whether it is associated with markers of disease stage and severity. METHODS: We recruited 48 individuals from families with PSEN1 or APP mutations to a cross-sectional study: 18 had symptomatic Alzheimer disease (AD) and 30 were asymptomatic but at 50% risk of carrying a mutation. Serum NfL was measured using an ultrasensitive immunoassay on the single molecule array (Simoa) platform...
October 25, 2017: Neurology
https://www.readbyqxmd.com/read/29067326/targeting-butyrylcholinesterase-for-preclinical-single-photon-emission-computed-tomography-spect-imaging-of-alzheimer-s-disease
#8
Drew R DeBay, George A Reid, Ian R Pottie, Earl Martin, Chris V Bowen, Sultan Darvesh
INTRODUCTION: Diagnosis of Alzheimer's disease (AD) in vivo, by molecular imaging of amyloid or tau, is constrained because similar changes can be found in brains of cognitively normal individuals. Butyrylcholinesterase (BChE), which becomes associated with these structures in AD, could elevate the accuracy of AD diagnosis by focusing on BChE pathology in the cerebral cortex, a region of scant BChE activity in healthy brain. METHODS: N-methylpiperidin-4-yl 4-[(123)I]iodobenzoate, a BChE radiotracer, was injected intravenously into B6SJL-Tg(APPSwFlLon, PSEN1∗M146 L∗L286 V) 6799Vas/Mmjax (5XFAD) mice and their wild-type (WT) counterparts for comparative single photon emission computed tomography (SPECT) studies...
June 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
https://www.readbyqxmd.com/read/29054964/gene-expression-profiling-of-the-notch-ahr-il22-axis-at-homeostasis-and-in-response-to-tissue-injury
#9
Marc Weidenbusch, Severin Rodler, Shangqing Song, Simone Romoli, Julian A Marschner, Franziska Kraft, Alexander Holderied, Santosh Kumar, Shrikant R Mulay, Mohsen Honarpisheh, Satish Kumar Devarapu, Maciej Lech, Hans-Joachim Anders
Notch and Interleukin-22 signaling are known to regulate tissue homeostasis and response to injury in humans and mice, and the induction of endogenous arylhydrocarbon receptor ligands through Notch links the two pathways in a hierarchical fashion. However, in adults the species-, organ- and injury-specific gene expression of the Notch-AhR-IL22 axis components is unknown. We therefore performed gene expression profiling of DLL1, DLL3, DLL4, DLK1, DLK2, JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, ADAM17/TACE, PSEN1, BSG/CD147, RBP-J, HES1, HES5, HEY1, HEYL, AHR, ARNT, ARNT2, CYP1A1, CYP24A1, IL22, IL22RA1, IL22RA2, IL10RB, and STAT3 under homeostatic conditions in 10 mature murine and human organs...
October 20, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29040655/effects-of-1950-mhz-radiofrequency-electromagnetic-fields-on-a%C3%AE-processing-in-human-neuroblastoma-and-mouse-hippocampal-neuronal-cells
#10
Jeongyeon Park, Jong Hwa Kwon, Nam Kim, Kiwon Song
Alzheimer's disease (AD) is a neurodegenerative disease leading to progressive loss of memory and other cognitive functions. One of the well-known pathological markers of AD is the accumulation of amyloid-beta protein (Aβ), and its plaques, in the brain. Recent studies using Tg-5XFAD mice as a model of AD have reported that exposure to radiofrequency electromagnetic fields (RF-EMF) from cellular phones reduced Aβ plaques in the brain and showed beneficial effects on AD. In this study, we examined whether exposure to 1950 MHz RF-EMF affects Aβ processing in neural cells...
October 6, 2017: Journal of Radiation Research
https://www.readbyqxmd.com/read/29021256/disruption-of-amyloid-precursor-protein-ubiquitination-selectively-increases-amyloid-beta-a%C3%AE-40-levels-via-presenilin-2-mediated-cleavage
#11
Rebecca L Williamson, Karine Laulagnier, André Miguel Miranda, Marty A Fernandez, Michael S Wolfe, Rémy Sadoul, Gilbert Di Paolo
Amyloid plaques, a neuropathological hallmark 1 of Alzheimer's disease (AD), are largely 2 composed of amyloid beta (Aβ) peptide, derived 3 from cleavage of amyloid precursor protein 4 (APP) by β- and γ-secretases. The endosome is 5 increasingly recognized as an important 6 crossroad for APP and these secretases, with 7 major implications for APP processing and 8 amyloidogenesis. Among various 9 posttranslational modifications affecting APP 10 accumulation, ubiquitination of cytodomain 11 lysines may represent a key signal controlling 12 APP endosomal sorting...
October 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28973985/s-adenosylmethionine-and-superoxide-dismutase-1-synergistically-counteract-alzheimer-s-disease-features-progression-in-tgcrnd8-mice
#12
Rosaria A Cavallaro, Vincenzina Nicolia, Maria Teresa Fiorenza, Sigfrido Scarpa, Andrea Fuso
Recent evidence emphasizes the role of dysregulated one-carbon metabolism in Alzheimer's Disease (AD). Exploiting a nutritional B-vitamin deficiency paradigm, we have previously shown that PSEN1 and BACE1 activity is modulated by one-carbon metabolism, leading to increased amyloid production. We have also demonstrated that S-adenosylmethionine (SAM) supplementation contrasted the AD-like features, induced by B-vitamin deficiency. In the present study, we expanded these observations by investigating the effects of SAM and SOD (Superoxide dismutase) association...
September 30, 2017: Antioxidants (Basel, Switzerland)
https://www.readbyqxmd.com/read/28949931/genetic-underpinnings-in-alzheimer-s-disease-a-review
#13
Ahmed A Moustafa, Mubashir Hassan, Doaa H Hewedi, Iman Hewedi, Julia K Garami, Hany Al Ashwal, Nazar Zaki, Sung-Yum Seo, Vassilis Cutsuridis, Sergio L Angulo, Joman Y Natesh, Mohammad M Herzallah, Dorota Frydecka, Błażej Misiak, Mohamed Salama, Wael Mohamed, Mohamad El Haj, Michael Hornberger
In this review, we discuss the genetic etiologies of Alzheimer's disease (AD). Furthermore, we review genetic links to protein signaling pathways as novel pharmacological targets to treat AD. Moreover, we also discuss the clumps of AD-m ediated genes according to their single nucleotide polymorphism mutations. Rigorous data mining approaches justified the significant role of genes in AD prevalence. Pedigree analysis and twin studies suggest that genetic components are part of the etiology, rather than only being risk factors for AD...
September 26, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/28892789/thymoquinone-rich-fraction-nanoemulsion-tqrfne-decreases-a%C3%AE-40-and-a%C3%AE-42-levels-by-modulating-app-processing-up-regulating-ide-and-lrp1-and-down-regulating-bace1-and-rage-in-response-to-high-fat-cholesterol-diet-induced-rats
#14
Norsharina Ismail, Maznah Ismail, Nur Hanisah Azmi, Muhammad Firdaus Abu Bakar, Zhang Yida, Maizaton Atmadini Abdullah, Hamidon Basri
Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis...
November 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28879407/microrna-profiling-in-aging-brain-of-psen1-psen2-double-knockout-mice
#15
Suji Ham, Tae Kyoo Kim, Sangjoon Lee, Ya-Ping Tang, Heh-In Im
MicroRNAs are small non-coding RNAs that function as regulators of gene expression. The altered expression of microRNAs influences the pathogenesis of Alzheimer's disease. Many researchers have focused on studies based on the relatively distinctive etiology of familial Alzheimer's disease due to the absence of risk factors in the pathogenesis of sporadic Alzheimer's disease. Although there is a limitation in Alzheimer's disease studies, both Alzheimer's disease types have a common risk factor-aging. No study to date has examined the aging factor in Alzheimer's disease animal models with microRNAs...
September 6, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28863942/mitochondrial-dysfunction-in-the-app-psen1-mouse-model-of-alzheimer-s-disease-and-a-novel-protective-role-for-ascorbate
#16
Shilpy Dixit, Joshua P Fessel, Fiona E Harrison
Mitochondrial dysfunction is elevated in very early stages of Alzheimer's disease and exacerbates oxidative stress, which contributes to disease pathology. Mitochondria were isolated from 4-month-old wild-type mice, transgenic mice carrying the APPSWE and PSEN1dE9 mutations, mice with decreased brain and mitochondrial ascorbate (vitamin C) via heterozygous knockout of the sodium dependent vitamin C transporter (SVCT2(+/-)) and transgenic APP/PSEN1 mice with heterozygous SVCT2 expression. Mitochondrial isolates from SVCT2(+/-) mice were observed to consume less oxygen using high-resolution respirometry, and also exhibited decreased mitochondrial membrane potential compared to wild type isolates...
November 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28821390/psen1-gene-polymorphisms-in-caucasian-alzheimer-s-disease-a-meta-analysis
#17
V Ramakrishnan, R S Akram Husain, Shiek S S J Ahmed
BACKGROUND: A meta-analysis was performed to assess PSEN1 gene polymorphisms (rs1800839 and rs17125721) in Alzheimer's disease (AD) risk. METHODS: A systematic electronic search was performed across databases to retrieve studies published before 31 January 2017. The association between the selected PSEN1 polymorphisms and AD was based on five genetic models using DerSimonian and Laird's method or Mantel-Haenszel's method. RESULTS: A total of 14 case-controlled studies were included...
October 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28798312/the-hypothesis-that-helicobacter-pylori-predisposes-to-alzheimer-s-disease-is-biologically-plausible
#18
Contaldi Felice, Capuano Federico, Fulgione Andrea, Aiese Cigliano Riccardo, Sanseverino Walter, Iannelli Domenico, Medaglia Chiara, Capparelli Rosanna
There is epidemiological evidence that H. pylori might predispose to Alzheimer's disease. To understand the cellular processes potentially linking such unrelated events, we incubated the human gastric cells MNK-28 with the H. pylori peptide Hp(2-20). We then monitored the activated genes by global gene expression. The peptide modulated 77 genes, of which 65 are listed in the AlzBase database and include the hallmarks of Alzheimer's disease: APP, APOE, PSEN1, and PSEN2. A large fraction of modulated genes (30 out of 77) belong to the inflammation pathway...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28781776/unraveling-the-genes-implicated-in-alzheimer-s-disease
#19
Mohan Giri, Abhilasha Shah, Bibhuti Upreti, Jayanti Chamling Rai
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and it is the most common form of dementia in the elderly. Early onset AD is caused by mutations in three genes: Amyloid-β precursor protein, presenilin 1 (PSEN1) and PSEN2. Late onset AD (LOAD) is complex and apolipoprotein E is the only unanimously accepted genetic risk factor for its development. Various genes implicated in AD have been identified using advanced genetic technologies, however, there are many additional genes that remain unidentified...
August 2017: Biomedical Reports
https://www.readbyqxmd.com/read/28767663/contribution-of-exome-sequencing-for-genetic-diagnostic-in-arrhythmogenic-right-ventricular-cardiomyopathy-dysplasia
#20
Joel Fedida, Veronique Fressart, Philippe Charron, Elodie Surget, Tiphaine Hery, Pascale Richard, Erwan Donal, Boris Keren, Guillaume Duthoit, Françoise Hidden-Lucet, Eric Villard, Estelle Gandjbakhch
BACKGROUND: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is an inherited cardiomyopathy mainly caused by heterozygous desmosomal gene mutations, the major gene being PKP2. The genetic cause remains unknown in ~50% of probands with routine desmosomal gene screening. The aim of this study was to assess the diagnostic accuracy of whole exome sequencing (WES) in ARVC/D with negative genetic testing. METHODS: WES was performed in 22 patients, all without a mutation identified in desmosomal genes...
2017: PloS One
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