Spatiotemporal activation of the C/EBPβ/δ-secretase axis regulates the pathogenesis of Alzheimer's disease.

Abstract:

:Alzheimer's disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the C/EBPβ/δ-secretase axis is activated in an age-dependent manner in different brain regions of the 3×Tg AD mouse model, elevating δ-secretase-truncated APP and Tau proteolytic truncates and promoting senile plaques and NFT formation in the brain, associated with gradual neuronal loss and chronic neuroinflammation. Depletion of inflammatory cytokine-regulated transcription factor C/EBPβ from 3×Tg mice represses APP, Tau, and δ-secretase expression, which subsequently inhibits APP and Tau cleavage, leading to mitigation of AD pathologies. Knockout of δ-secretase from 3×Tg mice strongly blunts AD pathogenesis. Consequently, inactivation of the C/EBPβ/δ-secretase axis ameliorates cognitive dysfunctions in 3×Tg mice by blocking APP and Tau expression and their pathological fragmentation. Thus, our findings support the notion that C/EBPβ/δ-secretase axis plays a crucial role in AD pathogenesis.

authors

Wang H,Liu X,Chen S,Ye K

doi

10.1073/pnas.1815915115

subject

Has Abstract

pub_date

2018-12-26 00:00:00

pages

E12427-E12434

issue

52

eissn

0027-8424

issn

1091-6490

pii

1815915115

journal_volume

115

pub_type

杂志文章
  • Crystal structure of measles virus hemagglutinin provides insight into effective vaccines.

    abstract::Measles still remains a major cause of childhood morbidity and mortality worldwide. Measles virus (MV) vaccines are highly successful, but the mechanism underlying their efficacy has been unclear. Here we report the crystal structure of the MV attachment protein, hemagglutinin, responsible for MV entry. The receptor-b...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0707830104

    authors: Hashiguchi T,Kajikawa M,Maita N,Takeda M,Kuroki K,Sasaki K,Kohda D,Yanagi Y,Maenaka K

    更新日期:2007-12-04 00:00:00

  • Near-unity nuclear polarization with an open-source 129Xe hyperpolarizer for NMR and MRI.

    abstract::The exquisite NMR spectral sensitivity and negligible reactivity of hyperpolarized xenon-129 (HP(129)Xe) make it attractive for a number of magnetic resonance applications; moreover, HP(129)Xe embodies an alternative to rare and nonrenewable (3)He. However, the ability to reliably and inexpensively produce large quant...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1306586110

    authors: Nikolaou P,Coffey AM,Walkup LL,Gust BM,Whiting N,Newton H,Barcus S,Muradyan I,Dabaghyan M,Moroz GD,Rosen MS,Patz S,Barlow MJ,Chekmenev EY,Goodson BM

    更新日期:2013-08-27 00:00:00

  • Effect of centrally administered C75, a fatty acid synthase inhibitor, on ghrelin secretion and its downstream effects.

    abstract::The central administration of the fatty acid synthase (FAS) inhibitor, C75, rapidly suppresses the expression of orexigenic neuropeptides [neuropeptide Y (NPY) and agouti-related protein (AgRP)] and activates expression of anorexigenic neuropeptides [proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated tr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0500619102

    authors: Hu Z,Cha SH,van Haasteren G,Wang J,Lane MD

    更新日期:2005-03-15 00:00:00

  • Fate of the replisome following arrest by UV-induced DNA damage in Escherichia coli.

    abstract::Accurate replication in the presence of DNA damage is essential to genome stability and viability in all cells. In Escherichia coli, DNA replication forks blocked by UV-induced damage undergo a partial resection and RecF-catalyzed regression before synthesis resumes. These processing events generate distinct structura...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1300624110

    authors: Jeiranian HA,Schalow BJ,Courcelle CT,Courcelle J

    更新日期:2013-07-09 00:00:00

  • Molecular engineering of an efficient four-domain DAF-MCP chimera reveals the presence of functional modularity in RCA proteins.

    abstract::The complement system is highly efficient in targeting pathogens, but lack of its apposite regulation results in host-cell damage, which is linked to diseases. Thus, complement activation is tightly regulated by a series of proteins, which primarily belong to the regulators of complement activation (RCA) family. Struc...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1818573116

    authors: Panwar HS,Ojha H,Ghosh P,Barage SH,Raut S,Sahu A

    更新日期:2019-05-14 00:00:00

  • Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.

    abstract::Age-related hearing loss and noise-induced hearing loss are major causes of human morbidity. Here we used genetics and functional studies to show that a shared cause of these disorders may be loss of function of the ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) that is expressed in sensor...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1222285110

    authors: Yan D,Zhu Y,Walsh T,Xie D,Yuan H,Sirmaci A,Fujikawa T,Wong AC,Loh TL,Du L,Grati M,Vlajkovic SM,Blanton S,Ryan AF,Chen ZY,Thorne PR,Kachar B,Tekin M,Zhao HB,Housley GD,King MC,Liu XZ

    更新日期:2013-02-05 00:00:00

  • Osmotic stress, crowding, preferential hydration, and binding: A comparison of perspectives.

    abstract::There has been much confusion recently about the relative merits of different approaches, osmotic stress, preferential interaction, and crowding, to describe the indirect effect of solutes on macromolecular conformations and reactions. To strengthen all interpretations of measurements and to forestall further unnecess...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.97.8.3987

    authors: Parsegian VA,Rand RP,Rau DC

    更新日期:2000-04-11 00:00:00

  • Structure of nascent replicative form DNA of coliphage M13.

    abstract::Nascent replicative form type II (RFII) DNA of coliphage M13 synthesized in an Escherichia coli mutant deficient in the 5' leads to 3' exonuclease associated uith DNA polymerase I contains ribonucleotides that are retained in the covalently closed RFI DNA sealed in vitro by the joint action of T5 phage DNA polymerase ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.1.153

    authors: Dasgupta S,Mitra S

    更新日期:1978-01-01 00:00:00

  • Alterations of the outer membrane composition in Escherichia coli lacking the histone-like protein HU.

    abstract::Escherichia coli cells lacking the histone-like protein HU form filaments and have an abnormal number of anucleate cells. Furthermore, their phenotype resembles that of rfa mutants, the well-characterized deep-rough phenotype, as they show an enhanced permeability that renders them hypersensitive to chloramphenicol, n...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.13.6712

    authors: Painbeni E,Caroff M,Rouviere-Yaniv J

    更新日期:1997-06-24 00:00:00

  • The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells.

    abstract::Ectopic activation of the Wnt signaling pathway is highly oncogenic for many human tissues. Here, we show that ectopic Wnt signaling increases the effective stem cell activity in mouse mammary glands in vivo. Furthermore, Wnt effectors induce the accumulation of mouse mammary epithelial progenitors (assayed by Hoechst...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0400699101

    authors: Liu BY,McDermott SP,Khwaja SS,Alexander CM

    更新日期:2004-03-23 00:00:00

  • Supersaturation in sickle cell hemoglobin solutions.

    abstract::The kinetic inhibition of the gelation of hemoglobin S is compared to the change in hemoglobin S soulbility, when the solubility is altered by carbon monoxide, pH, or urea. By means of a new technique, the delay time and the extent of gelation are measured on the same sample. They delay time, td, is found to be propor...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.9.3035

    authors: Hofrichter J,Ross PD,Eaton WA

    更新日期:1976-09-01 00:00:00

  • Lagging adaptation to warming climate in Arabidopsis thaliana.

    abstract::If climate change outpaces the rate of adaptive evolution within a site, populations previously well adapted to local conditions may decline or disappear, and banked seeds from those populations will be unsuitable for restoring them. However, if such adaptational lag has occurred, immigrants from historically warmer c...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1406314111

    authors: Wilczek AM,Cooper MD,Korves TM,Schmitt J

    更新日期:2014-06-03 00:00:00

  • Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation.

    abstract::Studies in mice indicate that the gut microbiota promotes energy harvest and storage from components of the diet when these components are plentiful. Here we examine how the microbiota shapes host metabolic and physiologic adaptations to periods of nutrient deprivation. Germ-free (GF) mice and mice who had received a ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0902366106

    authors: Crawford PA,Crowley JR,Sambandam N,Muegge BD,Costello EK,Hamady M,Knight R,Gordon JI

    更新日期:2009-07-07 00:00:00

  • Motion of a slightly compressible fluid.

    abstract::We show that the motion of a slightly compressible fluid is near that of an incompressible fluid. That is, for a given initial velocity field, the motion of a compressible fluid with large sound speed is near to that of an idealized incompressible fluid. We consider the compressible fluid motion in Lagrangian coordina...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.72.2.539

    authors: Ebin DG

    更新日期:1975-02-01 00:00:00

  • Inversin relays Frizzled-8 signals to promote proximal pronephros development.

    abstract::Mutations of inversin cause type II nephronophthisis, an infantile autosomal recessive disease characterized by cystic kidney disease and developmental defects. Inversin regulates Wnt signaling and is required for convergent extension movements during early embryogenesis. We now show that Inversin is essential for Xen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1013070107

    authors: Lienkamp S,Ganner A,Boehlke C,Schmidt T,Arnold SJ,Schäfer T,Romaker D,Schuler J,Hoff S,Powelske C,Eifler A,Krönig C,Bullerkotte A,Nitschke R,Kuehn EW,Kim E,Burkhardt H,Brox T,Ronneberger O,Gloy J,Walz G

    更新日期:2010-11-23 00:00:00

  • Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function.

    abstract::Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine's antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1816071116

    authors: Lumsden EW,Troppoli TA,Myers SJ,Zanos P,Aracava Y,Kehr J,Lovett J,Kim S,Wang FH,Schmidt S,Jenne CE,Yuan P,Morris PJ,Thomas CJ,Zarate CA Jr,Moaddel R,Traynelis SF,Pereira EFR,Thompson SM,Albuquerque EX,Gould TD

    更新日期:2019-03-12 00:00:00

  • The domain organization of NaeI endonuclease: separation of binding and catalysis.

    abstract::NaeI is a remarkable type II restriction endonuclease. It must bind two recognition sequences to cleave DNA, forms a covalent protein-DNA intermediate, and is only 1 aa change away from topoisomerase and recombinase activity. The latter activities apparently derive from reactivation of a cryptic DNA ligase active site...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.7.3531

    authors: Colandene JD,Topal MD

    更新日期:1998-03-31 00:00:00

  • Photooxidation of the high-potential iron-sulfur center in chloroplasts.

    abstract::The high-potential iron-sulfur center associated with the g = 1.89-1.90 electron paramagnetic resonance signal in spinach chloroplasts is fully reduced in the dark. It is photooxidized in the presence of 3-(3,4-dichlorophenyl)-1,1-dimethylurea and reduced after illumination with red actinic light in the absence of inh...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.9.4417

    authors: Whitmarsh J,Cramer WA

    更新日期:1979-09-01 00:00:00

  • Human T-cell leukemia virus (HTLV-I) transcripts in fresh and cultured cells of patients with adult T-cell leukemia.

    abstract::We examined the DNA and RNA of fresh leukemic cells (five patients) and long-term cultured T lymphocytes (four patients) from patients with adult T-cell leukemia for the presence of human T-cell leukemia virus (HTLV-I) sequences. In all cases HTLV-I provirus was found and several species of viral mRNAs were observed i...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.19.6207

    authors: Franchini G,Wong-Staal F,Gallo RC

    更新日期:1984-10-01 00:00:00

  • Guanyl nucleotides modulate binding to steroid receptors in neuronal membranes.

    abstract::The recently characterized corticosteroid receptor on amphibian neuronal membranes appears to mediate rapid, stress-induced changes in male reproductive behaviors. Because the transduction mechanisms associated with this receptor are unknown, we performed radioligand binding studies to determine whether this steroid r...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.9.3830

    authors: Orchinik M,Murray TF,Franklin PH,Moore FL

    更新日期:1992-05-01 00:00:00

  • Selective targeting of gene products with the megakaryocyte platelet factor 4 promoter.

    abstract::We have used the 1.1 kilobases of the 5' upstream region of the platelet factor four (PF4) gene coupled to the prokaryotic beta-galactosidase gene to generate two lines of transgenic mice that express this construct. Studies of blood, bone marrow, spleen, and thymus reveal that platelets are the only circulating blood...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.4.1521

    authors: Ravid K,Beeler DL,Rabin MS,Ruley HE,Rosenberg RD

    更新日期:1991-02-15 00:00:00

  • Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa.

    abstract::Retinitis pigmentosa (RP) is an inherited neurodegenerative disease, in which the death of mutant rod photoreceptors leads secondarily to the non-cell autonomous death of cone photoreceptors. Gene therapy is a promising treatment strategy. Unfortunately, current methods of gene delivery treat only a fraction of diseas...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1615394114

    authors: Koch SF,Duong JK,Hsu CW,Tsai YT,Lin CS,Wahl-Schott CA,Tsang SH

    更新日期:2017-05-16 00:00:00

  • A bio-chemo-mechanical model for cell contractility.

    abstract::A general model for the contractility of cells is presented that accounts for the dynamic reorganization of the cytoskeleton. The model is motivated by three key biochemical processes: (i) an activation signal that triggers actin polymerization and myosin phosphorylation, (ii) the tension-dependent assembly of the act...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0605837103

    authors: Deshpande VS,McMeeking RM,Evans AG

    更新日期:2006-09-19 00:00:00

  • Visualization for constructing and sharing geo-scientific concepts.

    abstract::Representations of scientific knowledge must reflect the dynamic nature of knowledge construction and the evolving networks of relations between scientific concepts. In this article, we describe initial work toward dynamic, visual methods and tools that support the construction, communication, revision, and applicatio...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0307755101

    authors: MacEachren AM,Gahegan M,Pike W

    更新日期:2004-04-06 00:00:00

  • Formylmethionyl-tRNA alters RNA polymerase specificity.

    abstract::Escherichia coli fMet-tRNAfMet alters the pattern of promoter selection of E. coli RNA polymerase (RNA nucleotidyltransferase, nucleosidetriphosphate:RNA nucleotidyltransferase; EC 2.7.7.6), affecting RNA synthesis from the rRNA, suIII+tRNA, and lac promoters in different ways. The in vitro synthesis of the stable RNA...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.2.870

    authors: Debenham PG,Pongs O,Travers AA

    更新日期:1980-02-01 00:00:00

  • Regulation of protein synthesis in reticulocyte lysates: phosphorylation of methionyl-tRNAf binding factor by protein kinase activity of translational inhibitor isolated from hemedeficient lysates.

    abstract::A previous study demonstrated that the translational inhibitor from lysates of heme-deficient rabbit reticulocytes is associated with a protein kinase activity. Chromatography of this inhibitor preparation on phosphocellulose yields two distinct protein kinase activities, PC1 and PC2. PC1, which consitutes about 90% o...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.9.3112

    authors: Levin D,Ranu RS,Ernst V,London IM

    更新日期:1976-09-01 00:00:00

  • Acetylcholine receptor-alpha-bungarotoxin interactions: determination of the region-to-region contacts by peptide-peptide interactions and molecular modeling of the receptor cavity.

    abstract::In previous studies from this laboratory, the binding regions of alpha-neurotoxins on human and Torpedo acetylcholine (AcCho) receptors (AcChoRs) and the binding regions for the receptor on the toxin were characterized with synthetic peptides of the respective molecules. In the present work, peptides representing the ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.16.6156

    authors: Ruan KH,Spurlino J,Quiocho FA,Atassi MZ

    更新日期:1990-08-01 00:00:00

  • The timing of phasic transmitter release is Ca2+-dependent and lacks a direct influence of presynaptic membrane potential.

    abstract::Ca2+ influx through voltage-gated Ca2+ channels and the resulting elevation of intracellular Ca2+ concentration, [Ca2+]i, triggers transmitter release in nerve terminals. However, it is controversial whether in addition to the opening of Ca2+ channels, membrane potential directly affects transmitter release. Here, we ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2433276100

    authors: Felmy F,Neher E,Schneggenburger R

    更新日期:2003-12-09 00:00:00

  • Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.

    abstract::Nitric oxide (NO) mediates several biological actions, including relaxation of blood vessels, cytotoxicity of activated macrophages, and formation of cGMP by activation of glutamate receptors in cerebellar slices. Nitric oxide synthase (EC 1.14.23.-) immunoreactivity is colocalized with nicotinamide adenine di-nucleot...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.14.6368

    authors: Dawson VL,Dawson TM,London ED,Bredt DS,Snyder SH

    更新日期:1991-07-15 00:00:00

  • Elevated Hedgehog/Gli signaling causes beta-cell dedifferentiation in mice.

    abstract::Although Hedgehog (Hh) signaling regulates cell differentiation during pancreas organogenesis, the consequences of pathway up-regulation in adult β-cells in vivo have not been investigated. Here, we elevate Hh signaling in β-cells by expressing an active version of the GLI2 transcription factor, a mediator of the Hh p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1105404108

    authors: Landsman L,Parent A,Hebrok M

    更新日期:2011-10-11 00:00:00