科研之友
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摘要
Although soluble species of the amyloid-beta peptide A beta 42 correlate with disease symptoms in Alzheimer disease, little is known about the biological activities of amyloid-beta (A beta). Here, we show that A beta 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 A beta 42 as follows: (i) biochemical analysis of nuclear fractions; (ii) detection of biotin-labeled A beta in living cells by confocal laser scanning microscopy; and (iii) transmission electron microscopy of A beta 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 A beta 42 in nuclear signaling, distinct from the amyloid precursor protein intracellular domain. Chromatin immunoprecipitation showed that A beta 42 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 A beta 42 wild-type peptide. Shorter peptides (A beta 38 or A beta 40) and other longer peptides (nontoxic A beta 42 G33A substitution or A beta 43) did not affect mRNA levels. Overall, our data indicate that the nuclear translocation of A beta 42 impacts gene regulation, and deleterious effects of A beta 42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes.
- 出版日期2014-7-18
- 单位McGill; 河北医科大学
