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  Nuclear translocation uncovers the amyloid peptide Aβ42 as a regulator of gene transcription

Barucker, C., Harmeier, A., Weiske, J., Fauler, B., Albring, K. F., Prokop, S., et al. (2014). Nuclear translocation uncovers the amyloid peptide Aβ42 as a regulator of gene transcription. The Journal of Biological Chemistry, 289(29), 20182-20191. doi:10.1074/jbc.M114.564690.

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 Creators:
Barucker, Christian, Author
Harmeier, Anja , Author
Weiske, Joerg , Author
Fauler, Beatrix1, Author           
Albring, Kai Frederik , Author
Prokop, Stefan, Author
Hildebrand, Peter, Author
Lurz, Rudi1, Author
Heppner, Frank L., Author
Huber, Otmar, Author
Multhaup, Gerhard, Author
Affiliations:
1Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              

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Free keywords: Alzheimer Disease; Amyloid; Amyloid β42 Toxicity; Amyloid β42-Chromatin Interaction; Chromatin Immunoprecipitation (ChiP); Gene Regulation; Nuclear Amyloid β Peptides; RNA
 Abstract: 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.

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Language(s): eng - English
 Dates: 2014-05-302014-07-18
 Publication Status: Issued
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1074/jbc.M114.564690
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Title: The Journal of Biological Chemistry
  Other : JBC
Source Genre: Journal
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Publ. Info: Baltimore, etc. : American Society for Biochemistry and Molecular Biology [etc.]
Pages: - Volume / Issue: 289 (29) Sequence Number: - Start / End Page: 20182 - 20191 Identifier: ISSN: 0021-9258
CoNE: https://pure.mpg.de/cone/journals/resource/954925410826_1