Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease.

Abstract:

:Abeta peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Abeta42 specifically in adult neurons, to avoid developmental effects. Abeta42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Abeta42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Abeta42 toxicity. Abeta42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Abeta42. The GSK-3-mediated effects on Abeta42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Abeta42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Abeta42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Abeta42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Sofola O,Kerr F,Rogers I,Killick R,Augustin H,Gandy C,Allen MJ,Hardy J,Lovestone S,Partridge L

doi

10.1371/journal.pgen.1001087

subject

Has Abstract

pub_date

2010-09-02 00:00:00

pages

e1001087

issue

9

eissn

1553-7390

issn

1553-7404

journal_volume

6

pub_type

杂志文章
  • Graded Nodal/Activin signaling titrates conversion of quantitative phospho-Smad2 levels into qualitative embryonic stem cell fate decisions.

    abstract::Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In co...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002130

    authors: Lee KL,Lim SK,Orlov YL,Yit le Y,Yang H,Ang LT,Poellinger L,Lim B

    更新日期:2011-06-01 00:00:00

  • Nephronophthisis-associated CEP164 regulates cell cycle progression, apoptosis and epithelial-to-mesenchymal transition.

    abstract::We recently reported that centrosomal protein 164 (CEP164) regulates both cilia and the DNA damage response in the autosomal recessive polycystic kidney disease nephronophthisis. Here we examine the functional role of CEP164 in nephronophthisis-related ciliopathies and concomitant fibrosis. Live cell imaging of RPE-FU...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004594

    authors: Slaats GG,Ghosh AK,Falke LL,Le Corre S,Shaltiel IA,van de Hoek G,Klasson TD,Stokman MF,Logister I,Verhaar MC,Goldschmeding R,Nguyen TQ,Drummond IA,Hildebrandt F,Giles RH

    更新日期:2014-10-23 00:00:00

  • The highly prolific phenotype of Lacaune sheep is associated with an ectopic expression of the B4GALNT2 gene within the ovary.

    abstract::Prolific sheep have proven to be a valuable model to identify genes and mutations implicated in female fertility. In the Lacaune sheep breed, large variation in litter size is genetically determined by the segregation of a fecundity major gene influencing ovulation rate, named FecL and its prolific allele FecL(L) . Ou...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003809

    authors: Drouilhet L,Mansanet C,Sarry J,Tabet K,Bardou P,Woloszyn F,Lluch J,Harichaux G,Viguié C,Monniaux D,Bodin L,Mulsant P,Fabre S

    更新日期:2013-01-01 00:00:00

  • A novel peptidoglycan binding protein crucial for PBP1A-mediated cell wall biogenesis in Vibrio cholerae.

    abstract::The bacterial cell wall, which is comprised of a mesh of polysaccharide strands crosslinked via peptide bridges (peptidoglycan, PG), is critical for maintenance of cell shape and survival. PG assembly is mediated by a variety of Penicillin Binding Proteins (PBP) whose fundamental activities have been characterized in ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004433

    authors: Dörr T,Lam H,Alvarez L,Cava F,Davis BM,Waldor MK

    更新日期:2014-06-19 00:00:00

  • Spatial fluctuations in expression of the heterocyst differentiation regulatory gene hetR in Anabaena filaments.

    abstract::Under nitrogen deprivation, filaments of the cyanobacterium Anabaena undergo a process of development, resulting in a one-dimensional pattern of nitrogen-fixing heterocysts separated by about ten photosynthetic vegetative cells. Many aspects of gene expression before nitrogen deprivation and during the developmental p...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005031

    authors: Corrales-Guerrero L,Tal A,Arbel-Goren R,Mariscal V,Flores E,Herrero A,Stavans J

    更新日期:2015-04-01 00:00:00

  • Nonsense-mediated decay enables intron gain in Drosophila.

    abstract::Intron number varies considerably among genomes, but despite their fundamental importance, the mutational mechanisms and evolutionary processes underlying the expansion of intron number remain unknown. Here we show that Drosophila, in contrast to most eukaryotic lineages, is still undergoing a dramatic rate of intron ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000819

    authors: Farlow A,Meduri E,Dolezal M,Hua L,Schlötterer C

    更新日期:2010-01-22 00:00:00

  • Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.

    abstract::Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 1...

    journal_title:PLoS genetics

    pub_type: 杂志文章,meta分析

    doi:10.1371/journal.pgen.1006528

    authors: Graff M,Scott RA,Justice AE,Young KL,Feitosa MF,Barata L,Winkler TW,Chu AY,Mahajan A,Hadley D,Xue L,Workalemahu T,Heard-Costa NL,den Hoed M,Ahluwalia TS,Qi Q,Ngwa JS,Renström F,Quaye L,Eicher JD,Hayes JE,Corneli

    更新日期:2017-04-27 00:00:00

  • Ribosome rescue and translation termination at non-standard stop codons by ICT1 in mammalian mitochondria.

    abstract::Release factors (RFs) govern the termination phase of protein synthesis. Human mitochondria harbor four different members of the class 1 RF family: RF1Lmt/mtRF1a, RF1mt, C12orf65 and ICT1. The homolog of the essential ICT1 factor is widely distributed in bacteria and organelles and has the peculiar feature in human mi...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004616

    authors: Akabane S,Ueda T,Nierhaus KH,Takeuchi N

    更新日期:2014-09-18 00:00:00

  • Correction: Origins of DNA replication.

    abstract::[This corrects the article DOI: 10.1371/journal.pgen.1008320.]. ...

    journal_title:PLoS genetics

    pub_type: 已发布勘误

    doi:10.1371/journal.pgen.1008556

    authors: PLOS Genetics Staff.

    更新日期:2019-12-19 00:00:00

  • The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding.

    abstract::The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3's function. Subdomains within this key region link Foxp3 to several independen...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005251

    authors: Xie X,Stubbington MJ,Nissen JK,Andersen KG,Hebenstreit D,Teichmann SA,Betz AG

    更新日期:2015-06-24 00:00:00

  • Recombination dynamics of a human Y-chromosomal palindrome: rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions.

    abstract::The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003666

    authors: Hallast P,Balaresque P,Bowden GR,Ballereau S,Jobling MA

    更新日期:2013-01-01 00:00:00

  • The talin head domain reinforces integrin-mediated adhesion by promoting adhesion complex stability and clustering.

    abstract::Talin serves an essential function during integrin-mediated adhesion in linking integrins to actin via the intracellular adhesion complex. In addition, the N-terminal head domain of talin regulates the affinity of integrins for their ECM-ligands, a process known as inside-out activation. We previously showed that in D...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004756

    authors: Ellis SJ,Lostchuck E,Goult BT,Bouaouina M,Fairchild MJ,López-Ceballos P,Calderwood DA,Tanentzapf G

    更新日期:2014-11-13 00:00:00

  • The bantam microRNA is associated with drosophila fragile X mental retardation protein and regulates the fate of germline stem cells.

    abstract::Fragile X syndrome, a common form of inherited mental retardation, is caused by the loss of fragile X mental retardation protein (FMRP). We have previously demonstrated that dFmr1, the Drosophila ortholog of the fragile X mental retardation 1 gene, plays a role in the proper maintenance of germline stem cells in Droso...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000444

    authors: Yang Y,Xu S,Xia L,Wang J,Wen S,Jin P,Chen D

    更新日期:2009-04-01 00:00:00

  • Slit-Dependent Endocytic Trafficking of the Robo Receptor Is Required for Son of Sevenless Recruitment and Midline Axon Repulsion.

    abstract::Understanding how axon guidance receptors are activated by their extracellular ligands to regulate growth cone motility is critical to learning how proper wiring is established during development. Roundabout (Robo) is one such guidance receptor that mediates repulsion from its ligand Slit in both invertebrates and ver...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005402

    authors: Chance RK,Bashaw GJ

    更新日期:2015-09-03 00:00:00

  • A drastic reduction in the life span of cystatin C L68Q carriers due to life-style changes during the last two centuries.

    abstract::Hereditary cystatin C amyloid angiopathy (HCCAA) is an autosomal dominant disease with high penetrance, manifest by brain hemorrhages in young normotensive adults. In Iceland, this condition is caused by the L68Q mutation in the cystatin C gene, with contemporary carriers reaching an average age of only 30 years. Here...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000099

    authors: Palsdottir A,Helgason A,Palsson S,Bjornsson HT,Bragason BT,Gretarsdottir S,Thorsteinsdottir U,Olafsson E,Stefansson K

    更新日期:2008-06-20 00:00:00

  • Elongator complex influences telomeric gene silencing and DNA damage response by its role in wobble uridine tRNA modification.

    abstract::Elongator complex is required for formation of the side chains at position 5 of modified nucleosides 5-carbamoylmethyluridine (ncm⁵U₃₄), 5-methoxycarbonylmethyluridine (mcm⁵U₃₄), and 5-methoxycarbonylmethyl-2-thiouridine (mcm⁵s²U₃₄) at wobble position in tRNA. These modified nucleosides are important for efficient dec...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002258

    authors: Chen C,Huang B,Eliasson M,Rydén P,Byström AS

    更新日期:2011-09-01 00:00:00

  • Mediation analysis demonstrates that trans-eQTLs are often explained by cis-mediation: a genome-wide analysis among 1,800 South Asians.

    abstract::A large fraction of human genes are regulated by genetic variation near the transcribed sequence (cis-eQTL, expression quantitative trait locus), and many cis-eQTLs have implications for human disease. Less is known regarding the effects of genetic variation on expression of distant genes (trans-eQTLs) and their biolo...

    journal_title:PLoS genetics

    pub_type: 杂志文章,随机对照试验

    doi:10.1371/journal.pgen.1004818

    authors: Pierce BL,Tong L,Chen LS,Rahaman R,Argos M,Jasmine F,Roy S,Paul-Brutus R,Westra HJ,Franke L,Esko T,Zaman R,Islam T,Rahman M,Baron JA,Kibriya MG,Ahsan H

    更新日期:2014-12-04 00:00:00

  • Glial loss of the metallo β-lactamase domain containing protein, SWIP-10, induces age- and glutamate-signaling dependent, dopamine neuron degeneration.

    abstract::Across phylogeny, glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many complex behaviors. Perturbed synaptic and extrasynaptic Glu homeostasis in the human brain has been implicated in multiple neuropsychiatric and neurodegenerative disorders including Parkinson's dis...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1007269

    authors: Gibson CL,Balbona JT,Niedzwiecki A,Rodriguez P,Nguyen KCQ,Hall DH,Blakely RD

    更新日期:2018-03-28 00:00:00

  • Translation in giant viruses: a unique mixture of bacterial and eukaryotic termination schemes.

    abstract::Mimivirus and Megavirus are the best characterized representatives of an expanding new family of giant viruses infecting Acanthamoeba. Their most distinctive features, megabase-sized genomes carried in particles of size comparable to that of small bacteria, fill the gap between the viral and cellular worlds. These gia...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003122

    authors: Jeudy S,Abergel C,Claverie JM,Legendre M

    更新日期:2012-01-01 00:00:00

  • Probing the canonicity of the Wnt/Wingless signaling pathway.

    abstract::The hallmark of canonical Wnt signaling is the transcriptional induction of Wnt target genes by the beta-catenin/TCF complex. Several studies have proposed alternative interaction partners for beta-catenin or TCF, but the relevance of potential bifurcations in the distal Wnt pathway remains unclear. Here we study on a...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1006700

    authors: Franz A,Shlyueva D,Brunner E,Stark A,Basler K

    更新日期:2017-04-03 00:00:00

  • Bacterial adaptation through loss of function.

    abstract::The metabolic capabilities and regulatory networks of bacteria have been optimized by evolution in response to selective pressures present in each species' native ecological niche. In a new environment, however, the same bacteria may grow poorly due to regulatory constraints or biochemical deficiencies. Adaptation to ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003617

    authors: Hottes AK,Freddolino PL,Khare A,Donnell ZN,Liu JC,Tavazoie S

    更新日期:2013-01-01 00:00:00

  • The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

    abstract::The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms under...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008544

    authors: Andersen MK,Jørsboe E,Skotte L,Hanghøj K,Sandholt CH,Moltke I,Grarup N,Kern T,Mahendran Y,Søborg B,Bjerregaard P,Larsen CVL,Dahl-Petersen IK,Tiwari HK,Feenstra B,Koch A,Wiener HW,Hopkins SE,Pedersen O,Melbye M,Boy

    更新日期:2020-01-24 00:00:00

  • A cis-regulatory signature for chordate anterior neuroectodermal genes.

    abstract::One of the striking findings of comparative developmental genetics was that expression patterns of core transcription factors are extraordinarily conserved in bilaterians. However, it remains unclear whether cis-regulatory elements of their target genes also exhibit common signatures associated with conserved embryoni...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000912

    authors: Haeussler M,Jaszczyszyn Y,Christiaen L,Joly JS

    更新日期:2010-04-15 00:00:00

  • Gluconeogenesis and PEPCK are critical components of healthy aging and dietary restriction life extension.

    abstract::High glucose diets are unhealthy, although the mechanisms by which elevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metaboli...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008982

    authors: Onken B,Kalinava N,Driscoll M

    更新日期:2020-08-25 00:00:00

  • The conditional nature of genetic interactions: the consequences of wild-type backgrounds on mutational interactions in a genome-wide modifier screen.

    abstract::The phenotypic outcome of a mutation cannot be simply mapped onto the underlying DNA variant. Instead, the phenotype is a function of the allele, the genetic background in which it occurs and the environment where the mutational effects are expressed. While the influence of genetic background on the expressivity of in...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003661

    authors: Chari S,Dworkin I

    更新日期:2013-01-01 00:00:00

  • Molecular basis of hemoglobin adaptation in the high-flying bar-headed goose.

    abstract::During the adaptive evolution of a particular trait, some selectively fixed mutations may be directly causative and others may be purely compensatory. The relative contribution of these two classes of mutation to adaptive phenotypic evolution depends on the form and prevalence of mutational pleiotropy. To investigate ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1007331

    authors: Natarajan C,Jendroszek A,Kumar A,Weber RE,Tame JRH,Fago A,Storz JF

    更新日期:2018-04-02 00:00:00

  • A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells.

    abstract::MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002054

    authors: Zheng GX,Ravi A,Calabrese JM,Medeiros LA,Kirak O,Dennis LM,Jaenisch R,Burge CB,Sharp PA

    更新日期:2011-05-01 00:00:00

  • Inferring causal direction between two traits in the presence of horizontal pleiotropy with GWAS summary data.

    abstract::Orienting the causal relationship between pairs of traits is a fundamental task in scientific research with significant implications in practice, such as in prioritizing molecular targets and modifiable risk factors for developing therapeutic and interventional strategies for complex diseases. A recent method, called ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1009105

    authors: Xue H,Pan W

    更新日期:2020-11-02 00:00:00

  • The microRNA mir-71 inhibits calcium signaling by targeting the TIR-1/Sarm1 adaptor protein to control stochastic L/R neuronal asymmetry in C. elegans.

    abstract::The Caenorhabditis elegans left and right AWC olfactory neurons communicate to establish stochastic asymmetric identities, AWC(ON) and AWC(OFF), by inhibiting a calcium-mediated signaling pathway in the future AWC(ON) cell. NSY-4/claudin-like protein and NSY-5/innexin gap junction protein are the two parallel signals ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002864

    authors: Hsieh YW,Chang C,Chuang CF

    更新日期:2012-01-01 00:00:00

  • Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process.

    abstract::The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005392

    authors: Kishimoto T,Ying BW,Tsuru S,Iijima L,Suzuki S,Hashimoto T,Oyake A,Kobayashi H,Someya Y,Narisawa D,Yomo T

    更新日期:2015-07-15 00:00:00