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Presenilin

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https://www.readbyqxmd.com/read/29242286/hop-1-presenilin-deficiency-causes-a-late-onset-notch-signaling-phenotype-that-affects-adult-germline-function-in-c-elegans
#1
Ipsita Agarwal, Cassandra Farnow, Joshua Jiang, Kyung-Sik Kim, Donna E Leet, Ruth Z Solomon, Valerie A Hale, Caroline Goutte
Functionally redundant genes present a puzzle as to their evolutionary preservation, and offer an interesting opportunity for molecular specialization. In Caenorhabditis elegans, either one of two presenilin genes (sel-12 or hop-1) facilitate Notch activation, providing the catalytic subunit for the gamma secretase proteolytic enzyme complex.  For all known Notch signaling events, sel-12 can mediate Notch activation, so the conservation of hop-1 remains a mystery. Here, we uncover a novel "late-onset" germline Notch phenotype in which HOP-1-deficient worms fail to maintain proliferating germline stem cells during adulthood...
December 14, 2017: Genetics
https://www.readbyqxmd.com/read/29234402/extract-of-fructus-cannabis-ameliorates-learning-and-memory-impairment-induced-by-d-galactose-in-an-aging-rats-model
#2
Ning-Yuan Chen, Cheng-Wu Liu, Wei Lin, Yi Ding, Zhang-Ya Bian, Ling Huang, Hao Huang, Kai-Hui Yu, Si-Bang Chen, Yu Sun, Lei Wei, Jun-Hua Peng, Shang-Ling Pan
Hempseed (Cannabis sativa L.) has been used as a health food and folk medicine in China for centuries. In the present study, we sought to define the underlying mechanism by which the extract of Fructus Cannabis (EFC) protects against memory impairment induced by D-galactose in rats. To accelerate aging and induce memory impairment in rats, D-galactose (400 mg/kg) was injected intraperitoneally once daily for 14 weeks. EFC (200 and 400 mg/kg) was simultaneously administered intragastrically once daily in an attempt to slow the aging process...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/29229705/proteolytic-processing-of-neurexins-by-presenilins-sustains-synaptic-vesicle-release
#3
Emilia Servián-Morilla, Estefanía Robles-Lanuza, Ana C Sánchez-Hidalgo, Rafael J Camacho-Garcia, Juan A Paez-Gomez, Fabiola Mavillard, Carlos A Saura, Amalia Martinez-Mir, Francisco G Scholl
Proteolytic processing of synaptic adhesion components can accommodate the function of synapses to activity-dependent changes. The adhesion system formed by Neurexins (Nrxns) and Neuroligins (Nlgns) bi-directionally orchestrate the function of pre- and postsynaptic terminals. Previous studies have shown that Presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheimer's disease, clear from glutamatergic terminals the accumulation of Neurexin C-terminal fragments (Nrxn-CTF) generated by ectodomain shedding...
December 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29212792/differential-effects-of-alcohol-and-its-metabolite-acetaldehyde-on-vascular-smooth-muscle-cell-notch-signaling-and-growth
#4
Ekaterina Hatch, David Morrow, Weimin Liu, Paul A Cahill, Eileen M Redmond
Alcohol (EtOH) consumption can variously affect cardiovascular disease (CVD). Our aim was to compare the effects of EtOH and its primary metabolite acetaldehyde (ACT) on vascular smooth muscle Notch signaling and cell growth that are important for atherogenesis. Human coronary artery smooth muscle cells (HCASMC) were treated with EtOH (25 mM) or ACT (10 μM, 25 μM). As previously reported, EtOH inhibited Notch signaling and growth of HCASMC. In contrast, ACT treatment stimulated HCASMC proliferation (cell counts) and increased proliferating cell nuclear antigen (PCNA) expression, concomitant with stimulation of Notch signaling as determined by increased Notch receptor (N1, N3) and target gene (HRT 1-3) mRNA levels...
December 6, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29211719/inhibition-of-soluble-epoxide-hydrolase-prevents-diabetic-retinopathy
#5
Jiong Hu, Sarah Dziumbla, Jihong Lin, Sofia-Iris Bibli, Sven Zukunft, Julian de Mos, Khader Awwad, Timo Frömel, Andreas Jungmann, Kavi Devraj, Zhixing Cheng, Liya Wang, Sascha Fauser, Charles G Eberhart, Akrit Sodhi, Bruce D Hammock, Stefan Liebner, Oliver J Müller, Clemens Glaubitz, Hans-Peter Hammes, Rüdiger Popp, Ingrid Fleming
Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid...
December 6, 2017: Nature
https://www.readbyqxmd.com/read/29196815/amyloid-%C3%AE-oligomers-a%C3%AE-os-in-alzheimer-s-disease
#6
REVIEW
Barbara Mroczko, Magdalena Groblewska, Ala Litman-Zawadzka, Johannes Kornhuber, Piotr Lewczuk
The causative role of amyloid β 1-42 (Aβ42) aggregation in the pathogenesis of Alzheimer's disease (AD) has been under debate for over 25 years. Primarily, scientific efforts have focused on the dyshomeostasis between production and clearance of Aβ42. This imbalance may result from mutations either in genes for the substrate, i.e., amyloid precursor protein or in genes encoding presenilin, the enzyme of the reaction that generates Aβ42. Currently, it is supposed that soluble oligomers of amyloid beta (AβOs) and not fibrillar Aβ42 within neuritic plaques may be the toxic factors acting on a very early stage of AD, perhaps even initiating pathological cascade...
December 1, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29182052/estimating-diagnostic-accuracy-for-clustered-ordinal-diagnostic-groups-in-the-three-class-case-application-to-the-early-diagnosis-of-alzheimer-disease
#7
Chengjie Xiong, Jingqin Luo, Ling Chen, Feng Gao, Jingxia Liu, Guoqiao Wang, Randall Bateman, John C Morris
Many medical diagnostic studies involve three ordinal diagnostic populations in which the diagnostic accuracy can be summarized by the volume or partial volume under the receiver operating characteristic surface for a diagnostic marker. When the diagnostic populations are clustered, e.g. by families, we propose to model the diagnostic marker by a general linear mixed model that takes into account of the correlation on the diagnostic marker from members of the same clusters. This model then facilitates the maximum likelihood estimation and statistical inferences of the diagnostic accuracy for the diagnostic marker...
January 1, 2017: Statistical Methods in Medical Research
https://www.readbyqxmd.com/read/29178139/phagocytic-clearance-of-presynaptic-dystrophies-by-reactive-astrocytes-in-alzheimer-s-disease
#8
Angela Gomez-Arboledas, Jose C Davila, Elisabeth Sanchez-Mejias, Victoria Navarro, Cristina Nuñez-Diaz, Raquel Sanchez-Varo, Maria Virtudes Sanchez-Mico, Laura Trujillo-Estrada, Juan Jose Fernandez-Valenzuela, Marisa Vizuete, Joan X Comella, Elena Galea, Javier Vitorica, Antonia Gutierrez
Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation of components of intermediate filaments, is a common feature in brains of Alzheimer's patients. Reactive astrocytes are found in close association with neuritic plaques; however, the precise role of these glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical techniques and light and electron microscopy, we report that plaque-associated reactive astrocytes enwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursor protein/presenilin-1 (APP/PS1) mice...
November 27, 2017: Glia
https://www.readbyqxmd.com/read/29175279/genetic-screening-in-two-iranian-families-with-early-onset-alzheimer-s-disease-identified-a-novel-psen1-mutation
#9
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/29170981/natural-dietary-supplementation-of-anthocyanins-via-pi3k-akt-nrf2-ho-1-pathways-mitigate-oxidative-stress-neurodegeneration-and-memory-impairment-in-a-mouse-model-of-alzheimer-s-disease
#10
Tahir Ali, Taehyun Kim, Shafiq Ur Rehman, Muhammad Sohail Khan, Faiz Ul Amin, Mehtab Khan, Muhammad Ikram, Myeong Ok Kim
Well-established studies have shown an elevated level of reactive oxygen species (ROS) that induces oxidative stress in the Alzheimer's disease (AD) patient's brain and an animal model of AD. Herein, we investigated the underlying anti-oxidant neuroprotective mechanism of natural dietary supplementation of anthocyanins extracted from Korean black beans in the amyloid precursor protein/presenilin-1 (APP/PS1) mouse model of AD. Both in vivo (APP/PS1 mice) and in vitro (mouse hippocampal HT22 cells) results demonstrated that anthocyanins regulate the phosphorylated-phosphatidylinositol 3-kinase-Akt-glycogen synthase kinase 3 beta (p-PI3K/Akt/GSK3β) pathways and consequently attenuate amyloid beta oligomer (AβO)-induced elevations in ROS level and oxidative stress via stimulating the master endogenous anti-oxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (Nrf2/HO-1) pathways and prevent apoptosis and neurodegeneration by suppressing the apoptotic and neurodegenerative markers such as activation of caspase-3 and PARP-1 expression as well as the TUNEL and Fluoro-Jade B-positive neuronal cells in the APP/PS1 mice...
November 23, 2017: Molecular Neurobiology
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
#11
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/29154272/differences-in-synaptic-dysfunction-between-rtg4510-and-app-ps1-mouse-models-of-alzheimer-s-disease
#12
Simon Gelman, Jonathan Palma, Geoffrey Tombaugh, Afshin Ghavami
Genetically modified mice have provided insights into the progression and pathology of Alzheimer's disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models...
November 14, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29142009/dominant-negative-mechanism-of-presenilin-1-mutations-in-fad
#13
Hirotaka Watanabe, Jie Shen
No abstract text is available yet for this article.
November 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29141208/crispr-transcriptional-activation-analysis-unmasks-an-occult-%C3%AE-secretase-processivity-defect-in-familial-alzheimer-s-disease-skin-fibroblasts
#14
Keiichi Inoue, Luis M A Oliveira, Asa Abeliovich
Mutations in presenilin (PSEN) 1 and 2, which encode components of the γ-secretase (GS) complex, cause familial Alzheimer's disease (FAD). It is hypothesized that altered GS-mediated processing of the amyloid precursor protein (APP) to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. Here, we describe an in vitro model system that enables the facile analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29138750/markers-of-alzheimer-s-disease-in-primary-visual-cortex-in-normal-aging-in-mice
#15
Luis Fernando Hernández-Zimbrón, Montserrat Perez-Hernández, Abigail Torres-Romero, Elisa Gorostieta-Salas, Roberto Gonzalez-Salinas, Rosario Gulias-Cañizo, Hugo Quiroz-Mercado, Edgar Zenteno
Aging is the principal risk factor for the development of Alzheimer's disease (AD). The hallmarks of AD are accumulation of the amyloid-β peptide 1-42 (Aβ42) and abnormal hyperphosphorylation of Tau (p-Tau) protein in different areas of the brain and, more recently reported, in the visual cortex. Recently, Aβ42 peptide overproduction has been involved in visual loss. Similar to AD, in normal aging, there is a significant amyloid deposition related to the overactivation of the aforementioned mechanisms. However, the mechanisms associated with visual loss secondary to age-induced visual cortex affectation are not completely understood...
2017: BioMed Research International
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
#16
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/29124106/gamma-rhythm-low-field-magnetic-stimulation-alleviates-neuropathologic-changes-and-rescues-memory-and-cognitive-impairments-in-a-mouse-model-of-alzheimer-s-disease
#17
Junli Zhen, Yanjing Qian, Xiechuan Weng, Wenting Su, Jianliang Zhang, Lihui Cai, Lin Dong, Haiting An, Ruijun Su, Jiang Wang, Yan Zheng, Xiaomin Wang
Introduction: The abnormal amyloid β (Aβ) accumulation and Aβ-related neural network dysfunction are considered central to the pathogenesis of Alzheimer's disease (AD) at the early stage. Deep-brain reachable low field magnetic stimulation (DMS), a novel noninvasive approach that was designed to intervene the network activity in brains, has been found to alleviate stress-related cognitive impairments. Methods: Amyloid precursor protein/presenilin-1 transgenic mice (5XFAD) were treated with DMS, and cognitive behavior and AD-like pathologic changes in the neurochemical and electrophysiological properties in 5XFAD mice were assessed...
November 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
https://www.readbyqxmd.com/read/29118109/activation-of-%C3%AE-secretase-trimming-activity-by-topological-changes-of-transmembrane-domain-1-of-presenilin-1
#18
Tetsuo Cai, Masahiro Yonaga, Taisuke Tomita
γ-Secretase is an intramembrane cleaving protease that is responsible for the generation of amyloid-β peptides, which are linked to the pathogenesis of Alzheimer disease. Recently, γ-secretase modulators (GSMs) have been shown to specifically decrease production of the aggregation-prone and toxic longer Aβ species, and concomitantly increase the levels of shorter Aβ. We previously found that phenylimidazole-type GSMs bind to presenilin 1 (PS1), the catalytic subunit of the γ-secretase, and allosterically modulate γ-secretase activity...
November 8, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29112196/understanding-the-roles-of-mutations-in-the-amyloid-precursor-protein-in-alzheimer-disease
#19
REVIEW
S Hunter, C Brayne
Many models of disease progression in Alzheimer's disease (AD) have been proposed to help guide experimental design and aid the interpretation of results. Models focussing on the genetic evidence include the amyloid cascade (ACH) and presenilin (PSH) hypotheses and the amyloid precursor protein (APP) matrix approach (AMA), of which the ACH has held a dominant position for over two decades. However, the ACH has never been fully accepted and has not yet delivered on its therapeutic promise. We review the ACH, PSH and AMA in relation to levels of APP proteolytic fragments reported from AD-associated mutations in APP...
November 7, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29109765/presenilin-mutation-suppresses-lung-tumorigenesis-via-inhibition-of-peroxiredoxin-6-activity-and-expression
#20
Mi Hee Park, Hyung-Mun Yun, Chul Ju Hwang, Sang Ick Park, Sang Bae Han, Dae Youn Hwang, Do-Young Yoon, Sanghyeon Kim, Jin Tae Hong
Some epidemiological studies suggest an inverse correlation between cancer incidence and Alzheimer's disease (AD). In this study, we demonstrated experimental evidences for this inverse relationship. In the co-expression network analysis using the microarray data and GEO profile of gene expression omnibus data analysis, we showed that the expression of peroxiredoxin 6 (PRDX6), a tumor promoting protein was significantly increased in human squamous lung cancer, but decreased in mutant presenilin 2 (PS2) containing AD patient...
2017: Theranostics
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