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Presenilin

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https://www.readbyqxmd.com/read/29439343/overactive-brca1-affects-presenilin-1-in-induced-pluripotent-stem-cell-derived-neurons-in-alzheimer-s-disease
#1
Michalina Wezyk, Aleksandra Szybinska, Joanna Wojsiat, Marcelina Szczerba, Kelly Day, Harriet Ronnholm, Malin Kele, Mariusz Berdynski, Beata Peplonska, Jakub Piotr Fichna, Jan Ilkowski, Maria Styczynska, Anna Barczak, Marzena Zboch, Anna Filipek-Gliszczynska, Krzysztof Bojakowski, Magdalena Skrzypczak, Krzysztof Ginalski, Michal Kabza, Izabela Makalowska, Maria Barcikowska-Kotowicz, Urszula Wojda, Anna Falk, Cezary Zekanowski
 The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1)...
2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29438981/pgam5-released-from-damaged-mitochondria-induces-mitochondrial-biogenesis-via-wnt-signaling
#2
Dominic B Bernkopf, Kowcee Jalal, Martina Brückner, Karl X Knaup, Marc Gentzel, Alexandra Schambony, Jürgen Behrens
Mitochondrial abundance is dynamically regulated and was previously shown to be increased by Wnt/β-catenin signaling. Pgam5 is a mitochondrial phosphatase which is cleaved by the rhomboid protease presenilin-associated rhomboid-like protein (PARL) and released from membranes after mitochondrial stress. In this study, we show that Pgam5 interacts with the Wnt pathway component axin in the cytosol, blocks axin-mediated β-catenin degradation, and increases β-catenin levels and β-catenin-dependent transcription...
February 8, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29438113/morphologic-and-immunohistochemical-appraisal-of-primary-gastric-carcinomas
#3
Gunes Guner, Aynur Isik, Erdem Karabulut, Gokhan Gedikoglu, Cenk Sokmensuer, Aytekin Akyol
Gastric carcinoma management requires adjustments answering their genetic and morphologic heterogeneity. We aim to assess the expression and significance of a myriad of biomarkers (p53, MLH1, MSH2, PMS2, MSH6, Epstein-Barr encoding region-RNA, c-erbB2, E-cadherin, CEA, chromogranin, Ki-67, CDX2, presenilin-1, cathepsin E, MUC5AC, cyclin-dependent kinase 1) in 117 gastric carcinomas, which we have morphologically subclassified with a simple algorithm. Immunohistochemical stains were applied to 3 tissue microarrays of primary gastric carcinomas (n=117) obtained from resection specimens of untreated patients...
February 12, 2018: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29435723/carvedilol-protection-against-endogenous-a%C3%AE-induced-neurotoxicity-in-n2a-cells
#4
Jia Liu, Min Wang
Mutations in amyloid precursor protein (APP) and presenilin1 result in overproduction and accumulation of β-amyloid (Aβ) peptide, which has been shown to play an important role in Alzheimer's disease (AD) pathogenesis. Carvedilol, a nonselective β-adrenergic receptor blocker used for treatment for heart failure and hypertension, has displayed its neuroprotective capacity due to its antioxidant property. In this study, we investigated whether Carvedilol has a neuronal protective effect against endogenous Aβ neurotoxicity in mouse Neuro2a (N2a) cells transfected with Swedish amyloid precursor protein (Swe-APP) mutant and Presenilin exon9 deletion mutant (N2a/Swe...
February 12, 2018: Cell Stress & Chaperones
https://www.readbyqxmd.com/read/29435558/association-between-amyloid-and-tau-accumulation-in-young-adults-with-autosomal-dominant-alzheimer-disease
#5
Yakeel T Quiroz, Reisa A Sperling, Daniel J Norton, Ana Baena, Joseph F Arboleda-Velasquez, Danielle Cosio, Aaron Schultz, Molly Lapoint, Edmarie Guzman-Velez, John B Miller, Leo A Kim, Kewei Chen, Pierre N Tariot, Francisco Lopera, Eric M Reiman, Keith A Johnson
Importance: It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. Objective: To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation...
February 12, 2018: JAMA Neurology
https://www.readbyqxmd.com/read/29429523/allicin-ameliorates-cognitive-impairment-in-app-ps1-mice-via-suppressing-oxidative-stress-by-blocking-jnk-signaling-pathways
#6
Hao Zhang, Ping Wang, Yixue Xue, Libo Liu, Zhen Li, Yunhui Liu
In middle and old age, Alzheimer's disease (AD) is a progressive neurodegenerative disorder of brain. As an increasingly aging population, AD represents a huge burden for the patients' family and the country. However, current therapeutical strategies have shown limited effectiveness. Allicin, which is the main composition of garlic, was reported to prevent the learning and memory impairment of AD mouse model. As the mechanism is not clear, in this study, we used the APP (amyloid precursor protein)/PS1 (presenilin 1) double transgenic mice, which express human mutant APP and PS1, to determine the protective effect of allicin on neurons...
February 2018: Tissue & Cell
https://www.readbyqxmd.com/read/29428965/the-product-of-the-%C3%AE-secretase-processing-of-ephrinb2-regulates-ve-cadherin-complexes-and-angiogenesis
#7
Noel A Warren, Georgios Voloudakis, Yonejung Yoon, Nikolaos K Robakis, Anastasios Georgakopoulos
Presenilin-1 (PS1) gene encodes the catalytic component of γ-secretase, which proteolytically processes several type I transmembrane proteins. We here present evidence that the cytosolic peptide efnB2/CTF2 produced by the PS1/γ-secretase cleavage of efnB2 ligand promotes EphB4 receptor-dependent angiogenesis in vitro. EfnB2/CTF2 increases endothelial cell sprouting and tube formation, stimulates the formation of angiogenic complexes that include VE-cadherin, Raf-1 and Rok-α, and increases MLC2 phosphorylation...
February 10, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29414706/solution-structure-of-an-intramembrane-aspartyl-protease-via-small-angle-neutron-scattering
#8
Swe-Htet Naing, Ryan C Oliver, Kevin L Weiss, Volker S Urban, Raquel L Lieberman
Intramembrane aspartyl proteases (IAPs) comprise one of four families of integral membrane proteases that hydrolyze substrates within the hydrophobic lipid bilayer. IAPs include signal peptide peptidase, which processes remnant signal peptides from nascent polypeptides in the endoplasmic reticulum, and presenilin, the catalytic component of the γ-secretase complex that processes Notch and amyloid precursor protein. Despite their broad biomedical reach, basic structure-function relationships of IAPs remain active areas of research...
February 6, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29406991/a-new-etiologic-model-for-alzheimers-disease
#9
Kathryn A Schiel
This etiologic model proposes that Alzheimers Disease (AD) arises when an unusually rapid increase in ventricle volume triggers axon stretch that culminates in the physical separation of trans-synaptic proteins. As a result, these proteins, such as neurexin, neuroligin, N-Cadherin and Amyloid Precursor Protein (APP), experience a change in the configuration of their cytoplasmic tail, so that instead of transmitting signals to create and maintain synaptic structure they activate enzymes, and generate molecules, that stimulate neurite growth; for example, the transformation of the N-Cadherin tail dissolves its complex with presenilin and β-catenin triggering activation of glycogen synthase kinase 3 beta (GSK3β) and cytoskeletal disruption...
February 2018: Medical Hypotheses
https://www.readbyqxmd.com/read/29404783/neuropathology-and-biochemistry-of-early-onset-familial-alzheimer-s-disease-caused-by-presenilin-1-missense-mutation-thr116asn
#10
Stanislav Sutovsky, Tomas Smolek, Peter Turcani, Robert Petrovic, Petra Brandoburova, Santosh Jadhav, Petr Novak, Johannes Attems, Norbert Zilka
The majority (~ 55%) of early onset familial Alzheimer disease (FAD) is caused by mutations in the presenilin 1 gene (PSEN1). Here, we describe a family with early onset FAD with a missense mutation in the PSEN1 gene (Thr116Asn). Five family members developed dementia in the third decade of life. One subject underwent autopsy. The onset of clinical symptoms was at the age of 37 years and the disease progressed rapidly. The clinical picture was characterised by progressive memory impairment, amnestic aphasia, and gait disturbances...
February 5, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29397305/spatial-patterns-of-neuroimaging-biomarker-change-in-individuals-from-families-with-autosomal-dominant-alzheimer-s-disease-a-longitudinal-study
#11
Brian A Gordon, Tyler M Blazey, Yi Su, Amrita Hari-Raj, Aylin Dincer, Shaney Flores, Jon Christensen, Eric McDade, Guoqiao Wang, Chengjie Xiong, Nigel J Cairns, Jason Hassenstab, Daniel S Marcus, Anne M Fagan, Clifford R Jack, Russ C Hornbeck, Katrina L Paumier, Beau M Ances, Sarah B Berman, Adam M Brickman, David M Cash, Jasmeer P Chhatwal, Stephen Correia, Stefan Förster, Nick C Fox, Neill R Graff-Radford, Christian la Fougère, Johannes Levin, Colin L Masters, Martin N Rossor, Stephen Salloway, Andrew J Saykin, Peter R Schofield, Paul M Thompson, Michael M Weiner, David M Holtzman, Marcus E Raichle, John C Morris, Randall J Bateman, Tammie L S Benzinger
BACKGROUND: Models of Alzheimer's disease propose a sequence of amyloid β (Aβ) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. METHODS: Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network...
January 31, 2018: Lancet Neurology
https://www.readbyqxmd.com/read/29395359/u1-small-nuclear-rna-overexpression-implicates-autophagic-lysosomal-system-associated-with-ad
#12
Zhi Cheng, Zhanqiang Du, Baohui Zhai, Zhuo Yang, Tao Zhang
Recently, we reported that presenilin 1 considerably increased the expression level of U1 small nuclear RNA (snRNA) accompanied with the adverse change of amyloid precursor protein (APP) expression, β-amyloid (Aβ) production and cell apoptosis. In the present study, it was found that U1 snRNA overexpression significantly elevated the expression level of autophagy. Moreover, rapamycin further enhanced the Aβ production and cell apoptosis, whereas these processes were effectively inhibited by 3-MA. Acridine orange staining images showed that U1 snRNA overexpression not only activated autophagy pathway, but also led to the autophagic-lysosomal system dysfunction in cells...
January 29, 2018: Neuroscience Research
https://www.readbyqxmd.com/read/29392878/presenilin-ps1%C3%A2-e9-disrupts-mobility-of-secretory-organelles-in-rat-astrocytes
#13
Matjaž Stenovec, Saša Trkov Bobnar, Tina Smolič, Marko Kreft, Vladimir Parpura, Robert Zorec
AIM: Alzheimer disease (AD) is largely considered a neuron-derived insult, but also involves failure of astroglia. A recent study indicated that mutated presenilin 1 (PS1M146V), a putative endoplasmic reticulum (ER) Ca2+ channel with decreased Ca2+ conductance, impairs the traffic of astroglial peptidergic vesicles. Whether other pathogenically relevant PS1 mutants, such as PS1ΔE9, which code for ER channel with putative increased Ca2+ conductance, similarly affect vesicle traffic, is unknown...
February 2, 2018: Acta Physiologica
https://www.readbyqxmd.com/read/29382721/both-positional-and-chemical-variables-control-in-vitro-proteolytic-cleavage-of-a-presenilin-ortholog
#14
Swe-Htet Naing, Sibel Kalyoncu, David M Smalley, Hyojung Kim, Xingjian Tao, Josh B George, Alex P Jonke, Ryan C Oliver, Volker S Urban, Matthew P Torres, Raquel L Lieberman
Mechanistic details of intramembrane aspartyl protease (IAP) chemistry, which is central to many biological and pathogenic processes, remain largely obscure. Here, we investigated the in vitro kinetics of a microbial intramembrane aspartyl protease (mIAP) fortuitously acting on the renin substrate angiotensinogen and the C-terminal transmembrane segment of amyloid precursor protein (C100), which is cleaved by the presenilin subunit of γ-secretase, an Alzheimer disease (AD)-associated IAP. mIAP variants with substitutions in active-site and putative substrate gating residues generally exhibit impaired, but not abolished, activity toward angiotensinogen, and retain the predominant cleavage site (His-Thr)...
January 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29378298/mir-34a-deficiency-in-app-ps1-mice-promotes-cognitive-function-by-increasing-synaptic-plasticity-via-ampa-and-nmda-receptors
#15
Yuelong Xu, Xiuxiu Li, Xianjun Wang, Jinguo Yao, Sujing Zhuang
MicroRNA (miR)-34a was recently determined to contribute to the pathological development of Alzheimer's disease (AD). miR-34a deficiency significantly attenuates cognitive deficits in amyloid precursor protein (APP)/presenilin 1 (PS1) mice; however, its role in early AD pathology and the underlying mechanisms remain elusive. Here, we confirmed that the increase of miR-34a expression in APP/PS1 mice was earlier than the relevant AD pathological characteristics, such as amyloid-β production, amyloid plaque deposition, and cognitive deficits...
January 26, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29376876/endogenous-murine-amyloid-%C3%AE-peptide-assembles-into-aggregates-in-the-aged-c57bl-6j-mouse-suggesting-these-animals-as-a-model-to-study-pathogenesis-of-amyloid-%C3%AE-plaque-formation
#16
Barbara Ahlemeyer, Sascha Halupczok, Elke Rodenberg-Frank, Klaus-Peter Valerius, Eveline Baumgart-Vogt
Amyloid-β peptide (Aβ), paired helical filament-tau (PHF-tau), and α-synuclein are in the focus of neuroscience research because they aggregate in brains of patients with Alzheimer's and Parkinson's diseases. For this purpose, transgenic mouse models were used containing the human genes for AβPP/presenilin/tau or α-synuclein with the most frequent mutations. This is not ideal because most patients develop sporadic forms of the diseases with no causative single gene defect and furthermore the aggregation of human proteins in man is not necessarily the same in rodents...
2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29361890/modelling-neurodegenerative-microenvironment-using-cortical-organoids-derived-from-human-stem-cells
#17
Yuanwei Yan, Liqing Song, Julie Bejoy, Jing Zhao, Takahisa Kanekiyo, Guojun Bu, Yi Zhou, Yan Li
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to lack of human brain models. Recently, mini-brain tissues called organoids have been derived from human induced pluripotent stem cells (hiPSCs) for modeling human brain development and neurological diseases. Thus, the objective of this research is to model and characterize neural degeneration microenvironment using 3-D forebrain cortical organoids derived from hiPSCs and study the response to the drug treatment...
January 23, 2018: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/29361519/curcumin-and-derivatives-function-through-protein-phosphatase-2a-and-presenilin-orthologues-in-dictyostelium-discoideum
#18
Marco Cocorocchio, Amy J Baldwin, Balint Stewart, Lou Kim, Adrian J Harwood, Christopher R L Thompson, Paul L R Andrews, Robin S B Williams
Natural compounds often have complex molecular structures and unknown molecular targets. These characteristics make them difficult to analyse using a classical pharmacological approach. Curcumin, the main curcuminoid of turmeric, is a complex molecule possessing wide-ranging biological activities, cellular mechanisms and roles in potential therapeutic treatment including Alzheimer's disease and cancer. Here, we investigate the physiological effects and molecular targets of curcumin in Dictyostelium discoideum We show curcumin causes acute effects on cell behaviour, reduces cell growth, and slows multicellular development...
December 28, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29358403/intracellular-ca2-stores-control-in-vivo-neuronal-hyperactivity-in-a-mouse-model-of-alzheimer-s-disease
#19
Chommanad Lerdkrai, Nithi Asavapanumas, Bianca Brawek, Yury Kovalchuk, Nima Mojtahedi, Maria Olmedillas Del Moral, Olga Garaschuk
Neuronal hyperactivity is the emerging functional hallmark of Alzheimer's disease (AD) in both humans and different mouse models, mediating an impairment of memory and cognition. The mechanisms underlying neuronal hyperactivity remain, however, elusive. In vivo Ca2+ imaging of somatic, dendritic, and axonal activity patterns of cortical neurons revealed that both healthy aging and AD-related mutations augment neuronal hyperactivity. The AD-related enhancement occurred even without amyloid deposition and neuroinflammation, mainly due to presenilin-mediated dysfunction of intracellular Ca2+ stores in presynaptic boutons, likely causing more frequent activation of synaptic NMDA receptors...
January 22, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29352484/melatonin-ameliorates-a%C3%AE-42-induced-alteration-of-%C3%AE-app-processing-secretases-via-the-melatonin-receptor-through-the-pin1-gsk3%C3%AE-nf-%C3%AE%C2%BAb-pathway-in-sh-sy5y-cells
#20
Vorapin Chinchalongporn, Mayuri Shukla, Piyarat Govitrapong
Melatonin is involved in the physiological regulation of the β- amyloid precursor protein (βAPP) cleaving secretases which are responsible for generation of the neurotoxic amyloid beta (Aβ) peptide, one of the hallmarks of Alzheimer's disease (AD) pathology. In this study, we aimed to determine the underlying mechanisms of this regulation under pathological conditions. We establish that melatonin prevents Aβ42 -induced down-regulation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) as well as up-regulation of β-site APP-cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) in SH-SY5Y cell cultures...
January 20, 2018: Journal of Pineal Research
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