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https://www.readbyqxmd.com/read/29329714/mutation-burden-profile-in-familial-alzheimer-s-disease-cases-from-india
#1
Adhikarla Syama, Somdatta Sen, Lakshmi Narayanan Kota, Biju Viswanath, Meera Purushottam, Mathew Varghese, Sanjeev Jain, Mitradas M Panicker, Odity Mukherjee
This study attempts to identify coding risk variants in genes previously implicated in Alzheimer's disease (AD) pathways, through whole-exome sequencing of subjects (N = 17) with AD, with a positive family history of dementia (familial AD). We attempted to evaluate the mutation burden in genes encoding amyloid precursor protein metabolism and previously linked to risk of dementias. Novel variants were identified in genes involved in amyloid precursor protein metabolism such as PSEN1 (chr 14:73653575, W161C, tgg > tgT), PLAT (chr 8:42039530,G272R), and SORL1 (chr11:121414373,G601D)...
December 12, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29316780/psen1-p-met233val-in-a-complex-neurodegenerative-movement-and-neuropsychiatric-disorder
#2
Silke Appel-Cresswell, Ilaria Guella, Anna Lehman, Dean Foti, Matthew J Farrer
Mutations in presenilin 1 (PSEN1) are the most common cause of autosomal dominant Alzheimer's disease. Here, we report a Canadian-Vietnamese family carrying a PSEN1 p.Met233Val mutation with an exceptionally early and severe presentation that includes a wide range of atypical symptoms, including prominent ataxia, Parkinsonism, spasticity, dystonia, action tremor, myoclonus, bulbar symptoms, seizures, hallucinations and behavioral changes. Whole-exome sequencing (WES) was performed on the affected proband after many assessments over several years proved diagnostically inconclusive...
January 11, 2018: Journal of Movement Disorders
https://www.readbyqxmd.com/read/29304399/establishment-of-induced-pluripotent-stem-cell-line-zzui009-a-from-an-alzheimer-s-disease-patient-carrying-a-psen1-gene-mutation
#3
Yanlin Wang, Na Jing, Linlin Su, Changhe Shi, Pei Zhang, Zhilei Wang, Huifang Sun, Jing Yang, Yutao Liu, Xuejun Wen, Jin Zhang, Shoutao Zhang, Yuming Xu
Skin fibroblasts were obtained from a 42-year-old Alzheimer's disease (AD) patient carrying mutations in the PSEN1 gene. An iPSC line was successfully established using the Sendai-virus (SeV) delivery system. The patient-specific iPSCs were free of genomically integrated reprogramming genes, had the specific mutation, expressed the expected pluripotency markers, and had the potential to differentiate into cells of all three germ layers. Our model might offer a robust platform for further study of the pathomechanism of this disease as well as drug testing and gene therapy studies...
December 12, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29191219/neurons-derived-from-sporadic-alzheimer-s-disease-ipscs-reveal-elevated-tau-hyperphosphorylation-increased-amyloid-levels-and-gsk3b-activation
#4
Anna Ochalek, Balázs Mihalik, Hasan X Avci, Abinaya Chandrasekaran, Annamária Téglási, István Bock, Maria Lo Giudice, Zsuzsanna Táncos, Kinga Molnár, Lajos László, Jørgen E Nielsen, Bjørn Holst, Kristine Freude, Poul Hyttel, Julianna Kobolák, András Dinnyés
BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD. METHODS: We compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer's disease (fAD), all caused by mutations in the PSEN1 gene; patients with late-onset sporadic Alzheimer's disease (sAD); and three control individuals without dementia...
December 1, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29186131/low-dose-proton-radiation-effects-in-a-transgenic-mouse-model-of-alzheimer-s-disease-implications-for-space-travel
#5
Emil Rudobeck, John A Bellone, Attila Szücs, Kristine Bonnick, Shalini Mehrotra-Carter, Jerome Badaut, Gregory A Nelson, Richard E Hartman, Roman Vlkolinský
Space radiation represents a significant health risk for astronauts. Ground-based animal studies indicate that space radiation affects neuronal functions such as excitability, synaptic transmission, and plasticity, and it may accelerate the onset of Alzheimer's disease (AD). Although protons represent the main constituent in the space radiation spectrum, their effects on AD-related pathology have not been tested. We irradiated 3 month-old APP/PSEN1 transgenic (TG) and wild type (WT) mice with protons (150 MeV; 0...
2017: PloS One
https://www.readbyqxmd.com/read/29177109/exome-sequencing-of-extended-families-with-alzheimer-s-disease-identifies-novel-genes-implicated-in-cell-immunity-and-neuronal-function
#6
H N Cukier, B K Kunkle, K L Hamilton, S Rolati, M A Kohli, P L Whitehead, J Jaworski, J M Vance, M L Cuccaro, R M Carney, J R Gilbert, L A Farrer, E R Martin, G W Beecham, J L Haines, M A Pericak-Vance
Objective: Alzheimer's disease (AD) is a neurodegenerative disorder for which more than 20 genetic loci have been implicated to date. However, studies demonstrate not all genetic factors have been identified. Therefore, in this study we seek to identify additional rare variants and novel genes potentially contributing to AD. Methods: Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants...
August 2017: Journal of Alzheimer's Disease and Parkinsonism
https://www.readbyqxmd.com/read/29175279/genetic-screening-in-two-iranian-families-with-early-onset-alzheimer-s-disease-identified-a-novel-psen1-mutation
#7
Jen-Chyong Wang, Somayeh Alinaghi, Abbas Tafakhori, Elizabeth Sikora, Luis J Azcona, Siamak Karkheiran, Alison Goate, Coro Paisán-Ruiz, Hossein Darvish
A subset of early-onset Alzheimer's disease is inherited as an autosomal-dominant trait and is associated with mutations in the genes encoding β-amyloid precursor protein, presenilin 1, or presenilin 2. In this study, we identified 2 PSEN1 mutations (1 novel and 1 known) in 2 unrelated Iranian families with autosomal-dominant Alzheimer's disease. The disease progressed rapidly with a mean age at onset of 33 and 42 years and an age at death ranging from 43 to 48 years.
October 23, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29164616/protection-against-%C3%AE-amyloid-neurotoxicity-by-a-non-toxic-endogenous-n-terminal-%C3%AE-amyloid-fragment-and-its-active-hexapeptide-core-sequence
#8
Kelly H Forest, Naghum Alfulaij, Komal Arora, Ruth Taketa, Tessi Sherrin, Cedomir Todorovic, James L M Lawrence, Gene T Yoshikawa, Ho-Leung Ng, Victor J Hruby, Robert A Nichols
High levels (μM) of beta amyloid (Aβ) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits and apoptotic cell death. The hydrophobic C-terminal domain of Aβ, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Aβ at low levels (pM-nM) has been shown to function as a positive neuromodulator and this activity resides in the hydrophilic N-terminal domain of Aβ. An N-terminal Aβ fragment (1-15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Aβ-induced impairments of long-term potentiation...
November 21, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29156377/establishment-of-induced-pluripotent-stem-cell-line-zzui010-a-from-an-alzheimer-s-disease-patient-carrying-an-app-gene-mutation
#9
Zhilei Wang, Pei Zhang, Yanlin Wang, Changhe Shi, Na Jing, Huifang Sun, Jing Yang, Yutao Liu, Xuejun Wen, Jin Zhang, Shoutao Zhang, Yuming Xu
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders. Previous studies have identified mutations in several genes, such as amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), in patients with early-onset (<65years) familial AD. Recently, a patient with an APP gene mutation was identified; the dermal fibroblasts of the patient were obtained and a line of induced pluripotent stem cells (iPSCs) was successfully generated using the Sendai-virus (SeV) delivery system...
November 3, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29153989/psen1-mutant-ipsc-derived-model-reveals-severe-astrocyte-pathology-in-alzheimer-s-disease
#10
Minna Oksanen, Andrew J Petersen, Nikolay Naumenko, Katja Puttonen, Šárka Lehtonen, Max Gubert Olivé, Anastasia Shakirzyanova, Stina Leskelä, Timo Sarajärvi, Matti Viitanen, Juha O Rinne, Mikko Hiltunen, Annakaisa Haapasalo, Rashid Giniatullin, Pasi Tavi, Su-Chun Zhang, Katja M Kanninen, Riikka H Hämäläinen, Jari Koistinaho
Alzheimer's disease (AD) is a common neurodegenerative disorder and the leading cause of cognitive impairment. Due to insufficient understanding of the disease mechanisms, there are no efficient therapies for AD. Most studies have focused on neuronal cells, but astrocytes have also been suggested to contribute to AD pathology. We describe here the generation of functional astrocytes from induced pluripotent stem cells (iPSCs) derived from AD patients with PSEN1 ΔE9 mutation, as well as healthy and gene-corrected isogenic controls...
December 12, 2017: Stem Cell Reports
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
#11
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
#12
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-old AD transgenic mice (APPswe,PSEN1∆E9) relative to wild-type mice, associated with a 34.5 ± 6.7% reduction in FABP5 expression in isolated brain capillaries of AD mice...
January 2018: 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
#13
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
#14
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
#15
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
#16
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
#17
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...
November 21, 2017: Neurology
https://www.readbyqxmd.com/read/29067326/targeting-butyrylcholinesterase-for-preclinical-single-photon-emission-computed-tomography-spect-imaging-of-alzheimer-s-disease
#18
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
#19
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
#20
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
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