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

• Published in: The Journal of biological chemistry Vol. 289; no. 29; pp. 20182 - 20191
• Main Authors: Barucker, Christian, Harmeier, Anja, Weiske, Joerg, Fauler, Beatrix, Albring, Kai Frederik, Prokop, Stefan, Hildebrand, Peter, Lurz, Rudi, Heppner, Frank L., Huber, Otmar, Multhaup, Gerhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.07.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Active Transport, Cell Nucleus; Alzheimer Disease; Alzheimer Disease - metabolism; Amino Acid Substitution; Amyloid; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - deficiency; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid β42 Toxicity; Amyloid β42-Chromatin Interaction; Animals; Cell Line; Chromatin Immunoprecipitation (ChiP); Gene Expression Regulation; Gene Regulation; HEK293 Cells; Humans; Mice; Mice, Knockout; Mice, Transgenic; Models, Molecular; Molecular Bases of Disease; Mutagenesis, Site-Directed; Neurons - metabolism; Neurons - ultrastructure; Nuclear Amyloid β Peptides; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Presenilin-1 - deficiency; Presenilin-1 - genetics; Presenilin-1 - metabolism; Protein Multimerization; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Static Electricity; Gene Regulation; RNA; Amyloid; Alzheimer Disease; Amyloid β42-Chromatin Interaction; Nuclear Amyloid β Peptides; Chromatin Immunoprecipitation (ChiP); Amyloid β42 Toxicity
• ISSN: 0021-9258; 1083-351X
• DOI: 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. Background: Biological activities of nontoxic Aβ42 peptides remain unclear in Alzheimer disease. Results: Aβ species are taken up in the nucleus of cells by a nonregulated mechanism, but only Aβ42 plays a role in gene transcription. Conclusion: Aβ42 may act as a transcriptional regulator, similar to the cytoplasmic fragment AICD. Significance: Genes regulated by nuclear Aβ42 could represent alternative targets for therapeutic approaches.