| First Author | Barucker C | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 29 | Pages | 20182-91 |
| PubMed ID | 24878959 | Mgi Jnum | J:321782 |
| Mgi Id | MGI:6843471 | Doi | 10.1074/jbc.M114.564690 |
| Citation | Barucker C, et al. (2014) Nuclear translocation uncovers the amyloid peptide Abeta42 as a regulator of gene transcription. J Biol Chem 289(29):20182-91 |
| abstractText | Although soluble species of the amyloid-beta peptide Abeta42 correlate with disease symptoms in Alzheimer disease, little is known about the biological activities of amyloid-beta (Abeta). Here, we show that Abeta 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 Abeta42 as follows: (i) biochemical analysis of nuclear fractions; (ii) detection of biotin-labeled Abeta in living cells by confocal laser scanning microscopy; and (iii) transmission electron microscopy of Abeta 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 Abeta42 in nuclear signaling, distinct from the amyloid precursor protein intracellular domain. Chromatin immunoprecipitation showed that Abeta42 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 Abeta42 wild-type peptide. Shorter peptides (Abeta38 or Abeta40) and other longer peptides (nontoxic Abeta42 G33A substitution or Abeta43) did not affect mRNA levels. Overall, our data indicate that the nuclear translocation of Abeta42 impacts gene regulation, and deleterious effects of Abeta42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes. |
