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Presenilin

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https://www.readbyqxmd.com/read/28641777/role-of-parl-pink1-parkin-pathway-in-adipocyte-differentiation
#1
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
#2
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
#3
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
#4
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
#5
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...
June 15, 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
#6
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
https://www.readbyqxmd.com/read/28620801/fty720-attenuates-infection-induced-enhancement-of-a%C3%AE-accumulation-in-app-ps1-mice-by-modulating-astrocytic-activation
#7
Róisín M McManus, Orla M Finucane, Mieszko M Wilk, Kingston H G Mills, Marina A Lynch
It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD...
June 15, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28620125/mutational-re-modeling-of-di-aspartyl-intramembrane-proteases-uncoupling-physiologically-relevant-activities-from-those-associated-with-alzheimer-s-disease
#8
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...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28619096/presenilins-regulate-synaptic-plasticity-and-mitochondrial-calcium-homeostasis-in-the-hippocampal-mossy-fiber-pathway
#9
Sang Hun Lee, David Lutz, Mohanad Mossalam, Vadim Y Bolshakov, Michael Frotscher, Jie Shen
BACKGROUND: Presenilins play a major role in the pathogenesis of Alzheimer's disease, in which the hippocampus is particularly vulnerable. Previous studies of Presenilin function in the synapse, however, focused exclusively on the hippocampal Schaffer collateral (SC) pathway. Whether Presenilins play similar or distinct roles in other hippocampal synapses is unknown. METHODS: To investigate the role of Presenilins at mossy fiber (MF) synapses we performed field and whole-cell electrophysiological recordings and Ca(2+) imaging using acute hippocampal slices of postnatal forebrain-restricted Presenilin conditional double knockout (PS cDKO) and control mice at 2 months of age...
June 15, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28595629/identification-and-description-of-three-families-with-familial-alzheimer-disease-that-segregate-variants-in-the-sorl1-gene
#10
Håkan Thonberg, Huei-Hsin Chiang, Lena Lilius, Charlotte Forsell, Anna-Karin Lindström, Charlotte Johansson, Jenny Björkström, Steinunn Thordardottir, Kristel Sleegers, Christine Van Broeckhoven, Annica Rönnbäck, Caroline Graff
Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative...
June 9, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28587718/%C3%AE-amyloid-precursor-protein-intracellular-domain-controls-mitochondrial-function-by-modulating-phosphatase-and-tensin-homolog-induced-kinase-1-transcription-in-cells-and-in-alzheimer-mice-models
#11
Thomas Goiran, Eric Duplan, Mounia Chami, Alexandre Bourgeois, Wejdane El Manaa, Lila Rouland, Julie Dunys, Inger Lauritzen, Han You, Vuk Stambolic, Maria-Grazia Biféri, Martine Barkats, Sanjay W Pimplikar, Nicolas Sergeant, Morvane Colin, Vanessa A Morais, Raphaelle Pardossi-Piquard, Frédéric Checler, Cristine Alves da Costa
BACKGROUND: Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease-affected brains by yet unexplained mechanisms. METHODS: We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which presenilins control phosphatase and tensin homolog-induced kinase 1 (Pink-1) expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in adeno-associated virus-infected mice...
May 3, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28554858/influence-of-low-frequency-psen1-variants-on-familial-alzheimer-s-disease-risk-in-brazil
#12
Bianca Barbosa Abdala, Jussara Mendonça Dos Santos, Andressa Pereira Gonçalves, Luciana Branco da Motta, Jerson Laks, Margarete Borges de Borges, Márcia Mattos Gonçalves Pimentel, Cíntia Barros Santos-Rebouças
About 30-70% of familial Alzheimer's disease (AD) cases are related to mutations in presenilin-1 gene (PSEN1). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil). Two missense variants (rs63750592; rs17125721), one rare and a low frequency variant, and two intronic variants (rs3025786; rs165932) were identified...
May 26, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28550254/precuneus-failures-in-subjects-of-the-psen1-e280a-family-at-risk-of-developing-alzheimer-s-disease-detected-using-quantitative-electroencephalography
#13
John Fredy Ochoa, Joan Francesc Alonso, Jon Edinson Duque, Carlos Andrés Tobón, Ana Baena, Francisco Lopera, Miguel Angel Mañanas, Alher Mauricio Hernández
BACKGROUND: Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer's disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-β. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD...
May 26, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28550247/two-novel-mutations-in-the-first-transmembrane-domain-of-presenilin1-cause-young-onset-alzheimer-s-disease
#14
Collin Y Liu, Yu Ohki, Taisuke Tomita, Satoko Osawa, Bruce R Reed, William Jagust, Victoria Van Berlo, Lee-Way Jin, Helena C Chui, Giovanni Coppola, John M Ringman
BACKGROUND: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. OBJECTIVE: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other...
May 25, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28533411/bidirectional-regulation-of-a%C3%AE-levels-by-presenilin-1
#15
Victor Bustos, Maria V Pulina, Yildiz Kelahmetoglu, Subhash C Sinha, Fred S Gorelick, Marc Flajolet, Paul Greengard
Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of β-secretase, generating the β-C-terminal fragment (βCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aβ. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28533369/phosphorylated-presenilin-1-decreases-%C3%AE-amyloid-by-facilitating-autophagosome-lysosome-fusion
#16
Victor Bustos, Maria V Pulina, Ashley Bispo, Alison Lam, Marc Flajolet, Fred S Gorelick, Paul Greengard
Presenilin 1 (PS1), the catalytic subunit of the γ-secretase complex, cleaves βCTF to produce Aβ. We have shown that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 decreases Aβ levels by increasing βCTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates βCTF degradation. We show that PS1 phosphorylated at Ser367, but not nonphosphorylated PS1, interacts with Annexin A2, which, in turn, interacts with the lysosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8...
May 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28532645/identification-of-a-novel-psen1-mutation-leu232pro-in-a-korean-patient-with-early-onset-alzheimer-s-disease-and-a-family-history-of-dementia
#17
Jiyun Park, Seong Soo A An, Vo Van Giau, Kyuhwan Shim, Young Chul Youn, Eva Bagyinszky, SangYun Kim
In the present study, a novel mutation in exon 7 of presenilin 1 (Leu232Pro) was discovered in a Korean patient with early-onset Alzheimer's disease, who represented memory decline at 37 years of age, followed by impairment in spatial activity and concentrations and personality changes. Imaging analyses with magnetic resonance scan showed diffuse atrophy in the frontoparietal regions. Targeted next generation sequencing and Sanger sequencing identified a heterozygous T to C transition at position 695 (c.695T>C) of in presenilin 1 gene (PSEN1), resulting in a novel missense mutation at codon 232 from leucine to proline (L232P)...
April 26, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28528772/early-interleukin-6-enhances-hepatic-ketogenesis-in-appswe-psen1de9-mice-via-3-hydroxy-3-methylglutary-coa-synthase-2-signaling-activation-by-p38-nuclear-factor-%C3%AE%C2%BAb-p65
#18
Le Shi, Daina Zhao, Chen Hou, Yunhua Peng, Jing Liu, Shuangxi Zhang, Jiankang Liu, Jiangang Long
Alzheimer's disease (AD) is considered a multifactorial disease that affects the central nervous system and periphery. A decline in brain glucose metabolism is an early feature of AD and is accompanied by a phenotypic shift from aerobic glycolysis to ketogenesis. The liver is responsible for the generation of the ketone body. However, the mechanism that underlies hepatic ketogenesis in AD remains unclear. Here, we investigated hepatic ketogenesis during the early stage of AD pathogenesis in amyloid precursor protein (APPSWE) and presenilin (PSEN1dE9) (APP/PS1) mice...
April 26, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28503509/nicotinamide-reduces-amyloid-precursor-protein-and-presenilin-1-in-brain-tissues-of-amyloid-beta-tail-vein-injected-mice
#19
Eun Jin Kim, Soo Jin Yang
The purpose of this study is to investigate whether nicotinic acid (NA) and nicotinamide (NAM) reduce the Alzheimer disease (AD)-related gene expression in brain tissues of amyloid beta (Aβ)-injected mice. Male Crj:CD1 (ICR) mice were divided into 6 treatment groups; 1) control, 2) Aβ control, 3) Aβ + NA 20 mg/kg/day (NA20), 4) Aβ + NA40, 5) Aβ + NAM 200 mg/kg/day (NAM200), and 6) Aβ + NAM400. After 1-week acclimation period, the mice orally received NA or NAM once a day for a total of 7 successive days...
April 2017: Clinical Nutrition Research
https://www.readbyqxmd.com/read/28502043/different-hippocampus-functional-connectivity-patterns-in-healthy-young-adults-with-mutations-of-app-presenilin-1-2-and-apoe%C3%AE%C2%B54
#20
Li Juan Zheng, Yun Yan Su, Yun Fei Wang, U Joseph Schoepf, Akos Varga-Szemes, Jonathan Pannell, Xue Liang, Gang Zheng, Guang Ming Lu, Gui Fen Yang, Long Jiang Zhang
This study aims to explore the hippocampus-based functional connectivity patterns in young, healthy APP and/or presenilin-1/2 mutation carriers and APOE ε4 subjects. Seventy-eight healthy young adults (33 male, mean age 24.0 ± 2.2 years; 18 APP and/or presenilin1/2 mutation carriers [APP/presenilin-1/2 group], 30 APOE ε4 subjects [APOE ε4 group], and 30 subjects without the above-mentioned genes [control group]) underwent resting-state functional MR imaging and neuropsychological assessments. Bilateral hippocampus functional connectivity patterns were compared among three groups...
May 13, 2017: Molecular Neurobiology
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