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Nuclear Translocation Uncovers the Amyloid Peptide Aβ42 as a Regulator of Gene Transcription*

  • Christian Barucker
    Affiliations
    Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, 14195 Berlin, Germany

    Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada
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  • Anja Harmeier
    Footnotes
    Affiliations
    Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, 14195 Berlin, Germany
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  • Joerg Weiske
    Footnotes
    Affiliations
    Institute of Clinical Chemistry and Pathobiochemistry, Charite-Campus Benjamin Franklin, 12203 Berlin, Germany
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  • Beatrix Fauler
    Affiliations
    Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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  • Kai Frederik Albring
    Affiliations
    Institute of Clinical Chemistry and Pathobiochemistry, Charite-Campus Benjamin Franklin, 12203 Berlin, Germany

    Institute of Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
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  • Stefan Prokop
    Affiliations
    Department of Neuropathology, Charite-Universitätsmedizin Berlin, 10117 Berlin, Germany
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  • Peter Hildebrand
    Affiliations
    Institute of Medical Physics and Biophysics, Charite-Universitätsmedizin Berlin, 10117 Berlin, Germany
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  • Rudi Lurz
    Affiliations
    Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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  • Frank L. Heppner
    Affiliations
    Department of Neuropathology, Charite-Universitätsmedizin Berlin, 10117 Berlin, Germany
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  • Otmar Huber
    Affiliations
    Institute of Clinical Chemistry and Pathobiochemistry, Charite-Campus Benjamin Franklin, 12203 Berlin, Germany

    Institute of Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany
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  • Gerhard Multhaup
    Correspondence
    To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-3621; Fax: 514-398-2045
    Affiliations
    Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, 14195 Berlin, Germany

    Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada
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  • Author Footnotes
    * This work was supported by Deutsche Forschungsgemeinschaft Grants SFB740 and GRK1123 (to G. M.), Kompetenznetz Degenerative Demenzen Förderkennzeichen Grant 01 GI 0723 (to G. M.), Deutsche Forschungsgemeinschaft grants (to F. L. H. and S. P.), and Deutsche Forschungsgemeinschaft Grant SFBTRR 43 and NeuroCure Exc 257 (to F. L. H.).
    ♦ This article was selected as a Paper of the Week.
    1 Present address: F. Hoffmann-La Roche AG, Pharma Research and Early Development, Discovery and Translational Area Neuroscience Basel, 4070 Basel, Switzerland.
    2 Present address: Bayer Pharma AG, 13353 Berlin, Germany.
Open AccessPublished:May 30, 2014DOI:https://doi.org/10.1074/jbc.M114.564690
      Although soluble species of the amyloid-β peptide Aβ42 correlate with disease symptoms in Alzheimer disease, little is known about the biological activities of amyloid-β (Aβ). Here, we show that Aβ peptides varying in lengths from 38 to 43 amino acids are internalized by cultured neuroblastoma cells and can be found in the nucleus. By three independent methods, we demonstrate direct detection of nuclear Aβ42 as follows: (i) biochemical analysis of nuclear fractions; (ii) detection of biotin-labeled Aβ in living cells by confocal laser scanning microscopy; and (iii) transmission electron microscopy of Aβ in cultured cells, as well as brain tissue of wild-type and transgenic APPPS1 mice (overexpression of amyloid precursor protein and presenilin 1 with Swedish and L166P mutations, respectively). Also, this study details a novel role for Aβ42 in nuclear signaling, distinct from the amyloid precursor protein intracellular domain. Chromatin immunoprecipitation showed that Aβ42 specifically interacts as a repressor of gene transcription with LRP1 and KAI1 promoters. By quantitative RT-PCR, we confirmed that mRNA levels of the examined candidate genes were exclusively decreased by the potentially neurotoxic Aβ42 wild-type peptide. Shorter peptides (Aβ38 or Aβ40) and other longer peptides (nontoxic Aβ42 G33A substitution or Aβ43) did not affect mRNA levels. Overall, our data indicate that the nuclear translocation of Aβ42 impacts gene regulation, and deleterious effects of Aβ42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes.

      Introduction

      The amyloid precursor protein (APP)
      The abbreviations used are: APP
      amyloid precursor protein
      amyloid-β
      AD
      Alzheimer disease
      AICD
      APP intracellular domain
      PS1
      presenilin 1
      TEM
      transmission electron microscopy
      tg
      transgenic
      qRT-PCR
      quantitative real time PCR
      MTT
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
      Tricine
      N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine
      MEF
      mouse embryo fibroblast.
      is first cleaved by the β-site APP-cleaving enzyme (BACE1) and sequentially processed by the γ-secretase complex to generate amyloid-β (Aβ) peptides of varying lengths encompassing 38, 40, 42, and 43 residues (
      • Zhang Y.W.
      • Thompson R.
      • Zhang H.
      • Xu H.
      APP processing in Alzheimer's disease.
      ). Aβ generation, through amyloidogenic processing of APP, results in the simultaneous production of a C-terminal fragment corresponding to the APP intracellular domain (AICD). This has been reported to translocate into the nucleus and activate gene transcription (
      • Haapasalo A.
      • Kovacs D.M.
      The many substrates of presenilin/γ-secretase.
      ,
      • Pardossi-Piquard R.
      • Checler F.
      The physiology of the β-amyloid precursor protein intracellular domain AICD.
      ).
      Aβ42 is hypothesized to be the main culprit in the pathogenesis of Alzheimer disease (AD) as it was postulated to impair synaptic function and initiate neuronal degeneration (
      • Hardy J.
      • Selkoe D.J.
      The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
      ). In AD, soluble species of Aβ42 are more strongly correlated with disease symptoms than with amyloid plaques (
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      • Cotman C.W.
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      Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
      ,
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      ,
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      Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo.
      ). Aβ42 was also reported to have an effect on differentiation and death of cultured neural stem or progenitor cells (
      • Uchida Y.
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      • Gomi F.
      • Takahashi H.
      Differential regulation of basic helix-loop-helix factors Mash1 and Olig2 by β-amyloid accelerates both differentiation and death of cultured neural stem/progenitor cells.
      ). Intraneuronal Aβ accumulation in brains of patients with AD, in animal models, and in cultured cells has suggested a pathophysiological role specific for Aβ40 and Aβ42 (
      • Gouras G.K.
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      • Checler F.
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      • Buxbaum J.D.
      • Xu H.
      • Greengard P.
      • Relkin N.R.
      Intraneuronal Aβ42 accumulation in human brain.
      ). Moreover, oxidative DNA damage in guinea pig primary neurons was shown to induce Aβ42 accumulation in the cytosol and to activate the p53 promoter (
      • Ohyagi Y.
      • Asahara H.
      • Chui D.H.
      • Tsuruta Y.
      • Sakae N.
      • Miyoshi K.
      • Yamada T.
      • Kikuchi H.
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      • Ikezoe K.
      • Furuya H.
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      • Shoji M.
      • Checler F.
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      • Makifuchi T.
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      • Tabira T.
      Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease.
      ). Similarly, under conditions of stress, Tau aggregates, which are the neuropathological hallmark of several neurodegenerative diseases, were found in the nucleus of neurons (
      • Sultan A.
      • Nesslany F.
      • Violet M.
      • Bégard S.
      • Loyens A.
      • Talahari S.
      • Mansuroglu Z.
      • Marzin D.
      • Sergeant N.
      • Humez S.
      • Colin M.
      • Bonnefoy E.
      • Buée L.
      • Galas M.C.
      Nuclear Tau, a key player in neuronal DNA protection.
      ). In primary neurons, microinjection of Aβ42 rapidly induced cell death, further underlining the neurotoxicity of intracellular amyloid (
      • Zhang Y.
      • McLaughlin R.
      • Goodyer C.
      • LeBlanc A.
      Selective cytotoxicity of intracellular amyloid β peptide 1–42 through p53 and Bax in cultured primary human neurons.
      ). Accordingly, transgenic (tg) mice producing only intracellular Aβ developed neurodegeneration (
      • LaFerla F.M.
      • Tinkle B.T.
      • Bieberich C.J.
      • Haudenschild C.C.
      • Jay G.
      The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice.
      ).
      The presence of intraneuronal Aβ is explained by a dynamic relationship that exists between pools of intracellular and extracellular Aβ (
      • Oddo S.
      • Caccamo A.
      • Smith I.F.
      • Green K.N.
      • LaFerla F.M.
      A dynamic relationship between intracellular and extracellular pools of Aβ.
      ). Intraneuronal Aβ originates both from APP inside the neurons (
      • Greenfield J.P.
      • Tsai J.
      • Gouras G.K.
      • Hai B.
      • Thinakaran G.
      • Checler F.
      • Sisodia S.S.
      • Greengard P.
      • Xu H.
      Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer β-amyloid peptides.
      ) and via uptake from the extracellular space. Aβ is internalized by neurons as well as by non-neuronal cells in culture, although the molecular events involved remain unclear (
      • Saavedra L.
      • Mohamed A.
      • Ma V.
      • Kar S.
      • de Chaves E.P.
      Internalization of β-amyloid peptide by primary neurons in the absence of apolipoprotein E.
      ,
      • Ida N.
      • Masters C.L.
      • Beyreuther K.
      Rapid cellular uptake of Alzheimer amyloid βA4 peptide by cultured human neuroblastoma cells.
      ,
      • Kim J.
      • Basak J.M.
      • Holtzman D.M.
      The role of apolipoprotein E in Alzheimer's disease.
      ). Aβ has been shown to accumulate within certain organelles, including the endosomes/lysosomes, and mitochondria (
      • Caspersen C.
      • Wang N.
      • Yao J.
      • Sosunov A.
      • Chen X.
      • Lustbader J.W.
      • Xu H.W.
      • Stern D.
      • McKhann G.
      • Yan S.D.
      Mitochondrial Aβ: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease.
      ), resulting in endosomal/lysosomal leakage, mitochondrial dysfunction, and apoptosis (
      • Umeda T.
      • Tomiyama T.
      • Sakama N.
      • Tanaka S.
      • Lambert M.P.
      • Klein W.L.
      • Mori H.
      Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo.
      ). Less well characterized is the peptide's ability to create channel-like pores in membranes (
      • Kagan B.L.
      • Hirakura Y.
      • Azimov R.
      • Azimova R.
      • Lin M.C.
      The channel hypothesis of Alzheimer's disease: current status.
      ,
      • Benilova I.
      • De Strooper B.
      Neuroscience. Promiscuous Alzheimer's amyloid: yet another partner.
      ,
      • Kayed R.
      • Pensalfini A.
      • Margol L.
      • Sokolov Y.
      • Sarsoza F.
      • Head E.
      • Hall J.
      • Glabe C.
      Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer.
      ,
      • Yoshiike Y.
      • Kayed R.
      • Milton S.C.
      • Takashima A.
      • Glabe C.G.
      Pore-forming proteins share structural and functional homology with amyloid oligomers.
      ).
      Channel-like pores may allow direct passage of Aβ oligomers into the nucleus, although at present it is not known whether Aβ peptides have a biological activity in the nucleus. Here, we show that Aβ peptides of varying lengths such as Aβ38, Aβ40, Aβ42, and Aβ43 are internalized by neuroblastoma cells and are subsequently detected in the nucleus. The nuclear localization of internalized Aβ42 peptides was further confirmed by both confocal and transmission electron microscopy (TEM). We also demonstrated the presence of endogenous Aβ42 peptides in the nuclei of neurons of tg APP mice (APPPS1). Using the chromatin immunoprecipitation (ChIP) assay, Aβ42 was found to specifically interact with the LRP1 and KAI1 promoter. Thus, at higher concentrations the widely recognized neurotoxic form Aβ42 here acted at sublethal concentrations as a repressor of transcription of the genes LRP1 and KAI1. This result was confirmed by quantification of the mRNA levels of the examined candidate genes by qRT-PCR. Furthermore, we found that Aβ42 increased the transcription of its own precursor gene APP. The mRNA levels were exclusively altered by the neurotoxic Aβ42 wild-type peptide, whereas neither Aβ38, Aβ40, nor Aβ43 had any effect on mRNA levels. Treatment with the nontoxic substitution peptide Aβ42 G33A, which was used as a control because it forms β-pleated sheet aggregates like the wild-type peptide (
      • Harmeier A.
      • Wozny C.
      • Rost B.R.
      • Munter L.M.
      • Hua H.
      • Georgiev O.
      • Beyermann M.
      • Hildebrand P.W.
      • Weise C.
      • Schaffner W.
      • Schmitz D.
      • Multhaup G.
      Role of amyloid-β glycine 33 in oligomerization, toxicity, and neuronal plasticity.
      ), also did not have an effect. Although for all Aβ peptides tested a nuclear translocation was observed, albeit to a varying extent, only Aβ42 entailed gene regulation. Thus, the major deleterious effects in the pathogenesis could be mediated by Aβ42 gene control activity, because it specifically interacts as a repressor or activator, respectively, of gene transcription.

      DISCUSSION

      Intraneuronal Aβ aggregates in the brains of AD patients and animal models have been detected with antibodies specific for Aβ40 and Aβ42. This suggests a pathophysiological role for the Aβ pool (
      • Gouras G.K.
      • Tsai J.
      • Naslund J.
      • Vincent B.
      • Edgar M.
      • Checler F.
      • Greenfield J.P.
      • Haroutunian V.
      • Buxbaum J.D.
      • Xu H.
      • Greengard P.
      • Relkin N.R.
      Intraneuronal Aβ42 accumulation in human brain.
      ,
      • Bayer T.A.
      • Wirths O.
      Intracellular accumulation of amyloid-β–a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease.
      ,
      • Wegiel J.
      • Kuchna I.
      • Nowicki K.
      • Frackowiak J.
      • Mazur-Kolecka B.
      • Imaki H.
      • Wegiel J.
      • Mehta P.D.
      • Silverman W.P.
      • Reisberg B.
      • Deleon M.
      • Wisniewski T.
      • Pirttilla T.
      • Frey H.
      • Lehtimäki T.
      • Kivimäki T.
      • Visser F.E.
      • Kamphorst W.
      • Potempska A.
      • Bolton D.
      • Currie J.R.
      • Miller D.L.
      Intraneuronal Aβ immunoreactivity is not a predictor of brain amyloidosis-β or neurofibrillary degeneration.
      ). Our present study demonstrates that in addition to intracellularly produced Aβ peptides, exogenous Aβ species of varying lengths can be taken up from the medium by the cells and translocated to the nucleus. Previously, intracellular soluble Aβ was shown not to colocalize with internalized transferrin, excluding clathrin-mediated endocytosis as the primary uptake mechanism (
      • Mandrekar S.
      • Jiang Q.
      • Lee C.Y.
      • Koenigsknecht-Talboo J.
      • Holtzman D.M.
      • Landreth G.E.
      Microglia mediate the clearance of soluble Aβ through fluid phase macropinocytosis.
      ). Nevertheless, clathrin-mediated Aβ endocytosis is possible and involves receptors that bind apolipoprotein E (apoE) (
      • Kim J.
      • Basak J.M.
      • Holtzman D.M.
      The role of apolipoprotein E in Alzheimer's disease.
      ). Aβ internalization by microglia was found nonsaturable, excluding receptor-mediated internalization (
      • Mandrekar S.
      • Jiang Q.
      • Lee C.Y.
      • Koenigsknecht-Talboo J.
      • Holtzman D.M.
      • Landreth G.E.
      Microglia mediate the clearance of soluble Aβ through fluid phase macropinocytosis.
      ). ApoE accelerates neuronal Aβ uptake, and the majority of endocytosed Aβ is suggested to traffic through early and late endosomes (
      • Li J.
      • Kanekiyo T.
      • Shinohara M.
      • Zhang Y.
      • LaDu M.J.
      • Xu H.
      • Bu G.
      Differential regulation of amyloid-β endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms.
      ). Our data indicate that the uptake process may only be partially influenced by the overall peptide length and hydrophobicity and cannot be correlated with one of the reported mechanisms in the literature. Although the molecular mechanism of Aβ uptake may depend on the cell type and could be influenced by changes in Aβ composition and prevailing aggregation states, we successfully detected all major Aβ peptides (i.e. present in body fluids and cell culture supernatants (
      • De Strooper B.
      • Annaert W.
      Novel research horizons for presenilins and γ-secretases in cell biology and disease.
      )) in the nucleus of SH-SY5Y cells. Additionally, this study also detected Aβ42 peptides in the nuclei of HEK293 and MEF PS1/2 knock-out cells. Aβ entry into cells could potentially occur through ligand-receptor type interactions as follows: e.g. Aβ interacts directly or indirectly with integrins, receptor for advanced glycation end products (RAGE), and APP itself (
      • Verdier Y.
      • Zarándi M.
      • Penke B.
      Amyloid β-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease.
      ); interactions via TrkA, p75NTR, some G-proteins, NMDA, and AMPA receptors (
      • Benilova I.
      • Karran E.
      • De Strooper B.
      The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes.
      ), and/or interactions via the prion protein (
      • Laurén J.
      • Gimbel D.A.
      • Nygaard H.B.
      • Gilbert J.W.
      • Strittmatter S.M.
      Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers.
      ,
      • Resenberger U.K.
      • Harmeier A.
      • Woerner A.C.
      • Goodman J.L.
      • Müller V.
      • Krishnan R.
      • Vabulas R.M.
      • Kretzschmar H.A.
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      • Multhaup G.
      • Winklhofer K.F.
      • Tatzelt J.
      The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication.
      ). Entry and transport could alternatively be limited to misfolded forms (e.g. aggregated Tau (
      • Frost B.
      • Jacks R.L.
      • Diamond M.I.
      Propagation of τ misfolding from the outside to the inside of a cell.
      )), possibly involving a transcellular propagation (
      • Kfoury N.
      • Holmes B.B.
      • Jiang H.
      • Holtzman D.M.
      • Diamond M.I.
      Trans-cellular propagation of τ aggregation by fibrillar species.
      ) that could lead to wider cerebral Aβ distribution (
      • Stöhr J.
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      • Oehler A.
      • Grillo S.K.
      • DeArmond S.J.
      • Prusiner S.B.
      • Giles K.
      Purified and synthetic Alzheimer's amyloid β (Aβ) prions.
      ). Most likely, peptide conformation plays a role as revealed by the nontoxic control Aβ42 G33A, which easily forms low and high n oligomers (
      • Harmeier A.
      • Wozny C.
      • Rost B.R.
      • Munter L.M.
      • Hua H.
      • Georgiev O.
      • Beyermann M.
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      • Weise C.
      • Schaffner W.
      • Schmitz D.
      • Multhaup G.
      Role of amyloid-β glycine 33 in oligomerization, toxicity, and neuronal plasticity.
      ). For example, in astrocytes, it was shown that oligomeric Aβ is more efficiently taken up than fibrillar Aβ (
      • Nielsen H.M.
      • Mulder S.D.
      • Beliën J.A.
      • Musters R.J.
      • Eikelenboom P.
      • Veerhuis R.
      Astrocytic Aβ 1–42 uptake is determined by Aβ-aggregation state and the presence of amyloid-associated proteins.
      ). Thus, Aβ might be able to enter the nucleus as an oligomeric complex comprising as many as nine Aβ peptide molecules as subunits. It is known that protein complexes of such sizes can pass through nuclear membrane pores because only translocation into the nucleus of proteins larger than 40 kDa requires specific transport receptors (
      • Mohr D.
      • Frey S.
      • Fischer T.
      • Güttler T.
      • Görlich D.
      Characterisation of the passive permeability barrier of nuclear pore complexes.
      ). In any case, given that (i) we did not apply stress conditions such as oxidative (
      • Ohyagi Y.
      • Asahara H.
      • Chui D.H.
      • Tsuruta Y.
      • Sakae N.
      • Miyoshi K.
      • Yamada T.
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      • Furuya H.
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      • Shoji M.
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      • Kira J.
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      ) or heat stress (
      • Sultan A.
      • Nesslany F.
      • Violet M.
      • Bégard S.
      • Loyens A.
      • Talahari S.
      • Mansuroglu Z.
      • Marzin D.
      • Sergeant N.
      • Humez S.
      • Colin M.
      • Bonnefoy E.
      • Buée L.
      • Galas M.C.
      Nuclear Tau, a key player in neuronal DNA protection.
      ) and (ii) Aβ does not possess a canonical nuclear localization signal or a nuclear export signal, these peptides are most likely diffusing freely into the nucleus. They are likely retained by binding to nondiffusible nuclear components and might accumulate there.
      In accordance with our findings, we anticipate that low n oligomers of aggregation-prone Aβ species, as well as monomers (e.g. of Aβ34), are able to enter the nucleus. Also, it seems that peptide length, conformation, and oligomerization are important determinants of Aβ uptake into the nucleus, although their biophysical traits inconsistently influence the process.
      Our ChIP results revealed that Aβ42 specifically associated with AICD-regulated promoters of LRP1 and KAI1. Subsequent qRT-PCR analyses demonstrated that Aβ42 diminished mRNA levels of LRP1 and KAI1. Previously, Aβ was found to localize to the nucleus under conditions of oxidative stress (
      • Bailey J.A.
      • Maloney B.
      • Ge Y.W.
      • Lahiri D.K.
      Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis.
      ). Moreover, Aβ42 was shown to bind to the APP promoter sequence using ChIP analysis and electrophoretic mobility shift assays (
      • Bailey J.A.
      • Maloney B.
      • Ge Y.W.
      • Lahiri D.K.
      Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis.
      ,
      • Maloney B.
      • Lahiri D.K.
      The Alzheimer's amyloid β-peptide (Aβ) binds a specific DNA Aβ-interacting domain (AβID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motif.
      ). Here, we demonstrate an increase of APP mRNA levels upon Aβ42 treatment. Aβ likely contains a helix-loop-helix structure (
      • Sticht H.
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      • Willbold D.
      • Dames S.
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      ), which is common to certain transcription factors. Thus, a direct binding of metastable oligomeric structures of Aβ, described in preparations of amyloid-forming peptides such as α-synuclein Tau, prion, and Aβ42, could mediate an interaction with DNA. In vitro, DNA binds all soluble aggregated forms of Aβ42 indicating that DNA interaction is a general property of different soluble forms of Aβ42 unrelated to the extent of aggregation (
      • Barrantes A.
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      Interaction between Alzheimer's Aβ1–42 peptide and DNA detected by surface plasmon resonance.
      ). The less- or non-neurotoxic Aβ species, including Aβ38, Aβ40, Aβ42 G33A, and Aβ43 (
      • Harmeier A.
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      • Hua H.
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      • Beyermann M.
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      Role of amyloid-β glycine 33 in oligomerization, toxicity, and neuronal plasticity.
      ,
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      ,
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      • Laroche S.
      • Davis S.
      Generation of aggregated β-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits.
      ), although possessing the ability to assemble into cross-β-fibrils (
      • Fraser P.E.
      • Duffy L.K.
      • O'Malley M.B.
      • Nguyen J.
      • Inouye H.
      • Kirschner D.A.
      Morphology and antibody recognition of synthetic β-amyloid peptides.
      ), did not influence gene regulation. Thus, our novel findings suggest that there might be a functional activity of Aβ42 in the nucleus that is different from AICD (
      • Haapasalo A.
      • Kovacs D.M.
      The many substrates of presenilin/γ-secretase.
      ,
      • Pardossi-Piquard R.
      • Checler F.
      The physiology of the β-amyloid precursor protein intracellular domain AICD.
      ). Among the several Aβ species that can accumulate in the nucleus, only Aβ42 appears to impact the expression of LRP1, KAI1, and APP.
      Most significantly, it is the overproduction of Aβ (e.g. mutations associated with early onset AD) that invariably leads to the modulation of Aβ load (
      • Kaden D.
      • Harmeier A.
      • Weise C.
      • Munter L.M.
      • Althoff V.
      • Rost B.R.
      • Hildebrand P.W.
      • Schmitz D.
      • Schaefer M.
      • Lurz R.
      • Skodda S.
      • Yamamoto R.
      • Arlt S.
      • Finckh U.
      • Multhaup G.
      Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers.
      ). This regulatory mechanism could induce APP transcription, thereby enhancing APP processing, Aβ production and uptake, and subsequent up-regulation of APP synthesis. Because the detection of intracellular Aβ is always accompanied by increased extracellular Aβ (
      • Aho L.
      • Pikkarainen M.
      • Hiltunen M.
      • Leinonen V.
      • Alafuzoff I.
      Immunohistochemical visualization of amyloid-β protein precursor and amyloid-β in extra- and intracellular compartments in the human brain.
      ), such a proposed mechanism would account for the favored uptake of Aβ from the extracellular pool.
      Notably, Aβ42, which is toxic in vivo at lower concentrations than applied here (
      • Benilova I.
      • Karran E.
      • De Strooper B.
      The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes.
      ) for in vitro studies, specifically modulated gene regulation as reported herein. Accordingly, we hypothesize that the neurotoxic Aβ42 low n oligomers provoke changes in gene transcription in vivo at concentrations that are subtoxic in vitro. This view is supported by the consideration that soluble low n oligomers of Aβ42 peptides are neurotoxic, in particular Aβ42 dimers and tetra-/hexamers (
      • Harmeier A.
      • Wozny C.
      • Rost B.R.
      • Munter L.M.
      • Hua H.
      • Georgiev O.
      • Beyermann M.
      • Hildebrand P.W.
      • Weise C.
      • Schaffner W.
      • Schmitz D.
      • Multhaup G.
      Role of amyloid-β glycine 33 in oligomerization, toxicity, and neuronal plasticity.
      ,
      • Kaden D.
      • Harmeier A.
      • Weise C.
      • Munter L.M.
      • Althoff V.
      • Rost B.R.
      • Hildebrand P.W.
      • Schmitz D.
      • Schaefer M.
      • Lurz R.
      • Skodda S.
      • Yamamoto R.
      • Arlt S.
      • Finckh U.
      • Multhaup G.
      Novel APP/Aβ mutation K16N produces highly toxic heteromeric Aβ oligomers.
      ,
      • Walsh D.M.
      • Klyubin I.
      • Fadeeva J.V.
      • Cullen W.K.
      • Anwyl R.
      • Wolfe M.S.
      • Rowan M.J.
      • Selkoe D.J.
      Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo.
      ,
      • Shankar G.M.
      • Li S.
      • Mehta T.H.
      • Garcia-Munoz A.
      • Shepardson N.E.
      • Smith I.
      • Brett F.M.
      • Farrell M.A.
      • Rowan M.J.
      • Lemere C.A.
      • Regan C.M.
      • Walsh D.M.
      • Sabatini B.L.
      • Selkoe D.J.
      Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
      ).
      In conclusion, our data indicate that Aβ42 has a specific transcriptional regulatory function. Our data imply that deregulation of Aβ target genes could be an alternative pathway for Aβ-induced neurotoxicity starting with processes such as Aβ accumulation.

      Acknowledgments

      We thank Paul Saftig (Christian-Albrechts-Universität zu Kiel) and Bart De Strooper (VIB Center for the Biology of Disease, K.U. Leuven) for providing us the MEF PS1/2 KO cells and Mathias Jucker for providing the APPPS1 mice. We greatly thank Chris Weise, Daniela Kaden (Freie Universität Berlin), Lisa Munter, and Shireen Hossain (McGill University) for discussions.

      Author Profile

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