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https://www.readbyqxmd.com/read/28781776/unraveling-the-genes-implicated-in-alzheimer-s-disease
#1
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/28774322/tau-accumulation-in-the-retina-promotes-early-neuronal-dysfunction-and-precedes-brain-pathology-in-a-mouse-model-of-alzheimer-s-disease
#2
Marius Chiasseu, Luis Alarcon-Martinez, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Laurie Destroismaisons, Christine Vande Velde, Fany Panayi, Caroline Louis, Adriana Di Polo
BACKGROUND: Tau is an axon-enriched protein that binds to and stabilizes microtubules, and hence plays a crucial role in neuronal function. In Alzheimer's disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood...
August 3, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28768718/app-mouse-models-for-alzheimer-s-disease-preclinical-studies
#3
REVIEW
Hiroki Sasaguri, Per Nilsson, Shoko Hashimoto, Kenichi Nagata, Takashi Saito, Bart De Strooper, John Hardy, Robert Vassar, Bengt Winblad, Takaomi C Saido
Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease (AD) research community has historically used first-generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD (FAD), mutant amyloid precursor protein (APP), or APP and presenilin (PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD Second-generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene...
August 1, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28767121/combined-association-of-presenilin-1-and-apolipoprotein-e-polymorphisms-with-maternal-meiosis-ii-error-in-down-syndrome-births
#4
Pranami Bhaumik, Priyanka Ghosh, Sujay Ghosh, Eleanor Feingold, Umut Ozbek, Biswanath Sarkar, Subrata Kumar Dey
Alzheimer's disease and Down syndrome often exhibit close association and predictively share common genetic risk-factors. Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE) genes are associated with early and late onset of Alzheimer's disease, respectively. Presenilin -1 is involved in faithful chromosomal segregation. A higher frequency of the APOE ε4 allele has been reported among young mothers giving birth to Down syndrome children. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of nondisjunction and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms...
July 31, 2017: Genetics and Molecular Biology
https://www.readbyqxmd.com/read/28760945/inactivation-of-nitric-oxide-synthesis-exacerbates-the-development-of-alzheimer-disease-pathology-in-appps1-mice-amyloid-precursor-protein-presenilin-1
#5
Diana Cifuentes, Marine Poittevin, Philippe Bonnin, Anta Ngkelo, Nathalie Kubis, Tatyana Merkulova-Rainon, Bernard I Lévy
The epidemiological link between hypertension and Alzheimer disease is established. We previously reported that hypertension aggravates the Alzheimer-like pathology in APPPS1 mice (amyloid precursor protein/presenilin-1, mouse model of Alzheimer disease) with angiotensin II-induced hypertension, in relation with hypertension and nitric oxide deficiency. To provide further insights into the role of nitric oxide in the hypertension-Alzheimer disease cross-talk, we studied the effects of nitric oxide blockade in APPPS1 mice using N(ω)-nitro-l-arginine methyl ester (l-NAME) alone or in combination with hydralazine, to normalize blood pressure...
July 31, 2017: Hypertension
https://www.readbyqxmd.com/read/28753475/presenilin-1-mutation-decreases-both-calcium-and-contractile-responses-in-cerebral-arteries
#6
Xavier Toussay, Jean-Luc Morel, Nathalie Biendon, Lolita Rotureau, François-Pierre Legeron, Marie-Charlotte Boutonnet, Yoon H Cho, Nathalie Macrez
Mutations or upregulation in presenilin 1 (PS1) gene are found in familial early-onset Alzheimer's disease or sporadic late-onset Alzheimer's disease, respectively. PS1 has been essentially studied in neurons and its mutation was shown to alter intracellular calcium (Ca(2+)) signals. Here, we showed that PS1 is expressed in smooth muscle cells (SMCs) of mouse cerebral arteries, and we assessed the effects of the deletion of exon 9 of PS1 (PS1dE9) on Ca(2+) signals and contractile responses of vascular SMC. Agonist-induced contraction of cerebral vessels was significantly decreased in PS1dE9 both in vivo and ex vivo...
June 24, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28753424/alzheimer-s-causing-mutations-shift-a%C3%AE-length-by-destabilizing-%C3%AE-secretase-a%C3%AE-n-interactions
#7
Maria Szaruga, Bogdan Munteanu, Sam Lismont, Sarah Veugelen, Katrien Horré, Marc Mercken, Takaomi C Saido, Natalie S Ryan, Tatjana De Vos, Savvas N Savvides, Rodrigo Gallardo, Joost Schymkowitz, Frederic Rousseau, Nick C Fox, Carsten Hopf, Bart De Strooper, Lucía Chávez-Gutiérrez
Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides...
July 27, 2017: Cell
https://www.readbyqxmd.com/read/28751379/the-interleukin-like-epithelial-mesenchymal-transition-inducer-ilei-exhibits-a-non-interleukin-like-fold-and-is-active-as-a-domain-swapped-dimer
#8
Anna M Jansson, Agnes Csiszar, Joachim Maier, Ann-Christin Nyström, Elisabeth Ax, Patrik Johansson, Lovisa Holmberg Schiavone
Production and secretion of pro-metastatic proteins is a feature of many tumor cells. The FAM3C Interleukin-like epithelial-to-mesenchymal-transition (EMT) inducer, ILEI has been shown to be strongly up-regulated in several cancers and to be essential for tumor formation and metastasis in epithelial cells, correlating with a significant decrease in overall survival in colon and breast cancer patients. ILEI has been seen to interact with the γ-secretase presenilin 1 subunit (PS1). However, not much is known about the mechanism-of-action or the detailed ILEI structure...
July 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28707599/designing-of-selective-%C3%AE-secretase-inhibitory-benzenesulfonamides-through-comparative-in-vitro-and-in-silico-analysis
#9
Neeraj Masand, Satya P Gupta, Ratan Lal Khosa
BACKGROUND: In Alzheimer's disease (AD), the gene mutations have been identified in the amyloid precursor protein (APP), the presenilin-1 (PS1) and -2 (PS2) genes. APP is a transmembrane protein which gets cleaved by α- and β-secretase enzymes and releases Aβ peptides which forms senile plaques in brain tissue. It contributes for local inflammatory response, subsequent oxidative stress, biochemical changes and neuronal death. Targeting the development of Aβ aggregates in the senile plaques is an important strategy in the treatment of AD...
July 13, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28707074/presenilin-1-delta-e9-mutant-induces-stim1-driven-store-operated-calcium-channel-hyperactivation-in-hippocampal-neurons
#10
Maria Ryazantseva, Anna Goncharova, Kseniia Skobeleva, Maksim Erokhin, Axel Methner, Pavel Georgiev, Elena Kaznacheyeva
Presenilins regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer disease. Elevated presenilin-1 (PS1) holoprotein levels have been detected in postmortem brains of patients carrying familial Alzheimer disease (FAD) PS1 mutations. This study examines the effect of the FAD presenilin mutant that lacks the ninth exon (PS1 ∆E9) and does not undergo endoproteolysis on store-operated calcium (SOC) entry. Significant enhancement of SOC channel activation was detected by electrophysiological measurements in hippocampal neurons with PS1 ∆E9 mutant expression...
July 13, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28701379/loss-of-clusterin-shifts-amyloid-deposition-to-the-cerebrovasculature-via-disruption-of-perivascular-drainage-pathways
#11
Aleksandra M Wojtas, Silvia S Kang, Benjamin M Olley, Maureen Gatherer, Mitsuru Shinohara, Patricia A Lozano, Chia-Chen Liu, Aishe Kurti, Kelsey E Baker, Dennis W Dickson, Mei Yue, Leonard Petrucelli, Guojun Bu, Roxana O Carare, John D Fryer
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and blood-brain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28698968/inhibition-of-poly-adp-ribose-polymerase-1-enhances-gene-expression-of-selected-sirtuins-and-app-cleaving-enzymes-in-amyloid-beta-cytotoxicity
#12
Przemysław L Wencel, Walter J Lukiw, Joanna B Strosznajder, Robert Piotr Strosznajder
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture...
July 12, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28666707/differential-alteration-of-hippocampal-function-and-plasticity-in-females-and-males-of-the-appxps1-mouse-model-of-alzheimer-s-disease
#13
Kevin Richetin, Petnoi Petsophonsakul, Laurent Roybon, Bruno P Guiard, Claire Rampon
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and impaired cognitive functions. The higher incidence of AD among women indicates that sex is one of the main risk factor for developing the disease. Using the transgenic amyloid precursor protein × presenilin 1 (APPxPS1) mouse model of AD, we investigated sex inequality with regards to memory capacities and hippocampal plasticity. We report that spatial memory is strongly affected in APPxPS1 females while remarkably spared in males, at all ages tested...
September 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28645897/versatility-of-presenilin-1
#14
Georgia R Frost, Eitan Wong, Yue-Ming Li
No abstract text is available yet for this article.
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28641777/role-of-parl-pink1-parkin-pathway-in-adipocyte-differentiation
#15
Ming-Yuh Shiau, Pin-Shen Lee, Ying-Jyun Huang, Ching-Ping Yang, Chiao-Wan Hsiao, Kai-Yun Chang, Huan-Wen Chen, Yih-Hsin Chang
OBJECTIVE: Adipogenesis determines the number of adipocytes which is increased when individuals become obese. Mitochondria undergo remarkable morphological and functional changes during adipogenesis. PTEN-induced kinase 1 (PINK1) is pivotal to maintain mitochondrial homeostasis in neural cells. The present study aimed at investigating effects of PINK1 on adipogenesis and energy metabolism. METHODS: Expression of presenilin associated rhomboid-like protein (PARL), PINK1 and Parkin, as well as the interaction among these proteins was temporally examined during adipogenesis...
July 2017: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/28641077/inhibition-of-early-growth-response-1-in-the-hippocampus-alleviates-neuropathology-and-improves-cognition-in-an-alzheimer-model-with-plaques-and-tangles
#16
Xike Qin, Yunling Wang, Hemant K Paudel
A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model...
June 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28629307/tumor-reversion-mesenchymal-epithelial-transition-as-a-critical-step-in-managing-the-tumor-microenvironment-cross-talk
#17
Mariano Bizzarri, Alessandra Cucina, Sara Proietti
Tumour reversion represents a promising field of investigation. The occurrence of cancer reversion both in vitro and in vivo has been ascertained by an increasing number of reports. The reverting process may be triggered in a wide range of different cancer types by both molecular and physical cues. This process encompasses mandatorily a change in the cell-stroma interactions, leading to profound modification in tissue architecture. Indeed, cancer reversion may be obtained by only resetting the overall burden of biophysical cues acting on the cell-stroma system, thus indicating that conformational changes induced by cell shape and cytoskeleton remodelling trigger downstream the cascade of molecular events required for phenotypic reversion...
June 8, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28628788/cryo-em-structures-of-human-%C3%AE-secretase
#18
REVIEW
Guanghui Yang, Rui Zhou, Yigong Shi
γ-secretase, a membrane-embedded aspartate protease, catalyzes peptide bond hydrolysis of a large variety of type I integral membrane proteins exemplified by amyloid precursor protein (APP). Cleavage of APP leads to formation of β-amyloid plaque, which is a hallmark of Alzheimer's disease (AD). Over 200 AD-associated mutations are mapped to presenilin 1 (PS1), the catalytic component of γ-secretase. In the past three years, several cryo-electron microscopy (cryo-EM) structures of human γ-secretase have been determined at near atomic resolutions...
June 16, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/28627692/the-role-of-intestinal-endotoxemia-in-a-rat-model-of-aluminum-neurotoxicity
#19
Feng Wang, Rui-Xia Guo, Wen-Xing Li, Bao-Feng Yu, Bai Han, Li-Xin Liu, De-Wu Han
The present study aimed to investigate the effects of intestinal endotoxemia (IETM) in a rat model of aluminum neurotoxicity established by D-galactose and aluminum trichloride (AlCl3). Adult Wistar rats were administered D‑galactose and AlCl3 to create the aluminum neurotoxicity model. The learning and memory abilities of the rats were subsequently observed using a Morris water maze test and the serum levels of lipopolysaccharide (LPS), tumor necrosis factor (TNF)‑α, interleukin (IL)‑1, diamine oxidase (DAO), glutamine (Gln) and glutaminase were measured...
August 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28623607/presenilin-1-targeted-morpholino-induces-cognitive-deficits-increased-brain-a%C3%AE-1-42-and-decreased-synaptic-marker-psd-95-in-zebrafish-larvae
#20
Laura Roesler Nery, Natalia Eltz Silva, Raphaela Fonseca, Monica Ryff Moreira Vianna
Presenilins are transmembrane proteases required for the proteolytic cleavage of Notch and also act as the catalytic core of the γ-secretase complex, which is responsible for the final cleavage of the amyloid precursor protein into Amyloid-β (Aβ) peptides of varying lengths. Presenilin-1 gene (psen1) mutations are the main cause of early-onset autosomal-dominant Familial Alzheimer Disease. Elucidating the roles of Presenilin-1 and other hallmark proteins involved in Alzheimer's disease is crucial for understanding the disease etiology and underlying molecular mechanisms...
June 16, 2017: Neurochemical Research
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