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. 2019 Jan 24;9:594. doi: 10.1038/s41598-018-37444-3

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Loss of heterochromatin and DDR in AD brains. (a) IHC staining for BMI1 (brown staining-black arrows) and MAP2 or NeuN (violet staining) on paraffin sections from the frontal cortex of age-match control (n = 2) and AD (n = 2) patients. Weak nuclear staining for BMI1 (dash lines) was observed in AD neurons. Scale bar: 3μm. (b) IHC staining for H3K9^me3 on frontal cortex sections of control (n = 5) and AD (n = 5) brains: (i) reduced peri-nucleolar heterochromatin in AD (arrows), (ii) chromocenters de-condensation in AD, and (iii) loss of H3K9^me3 immunoreactivity in AD neurons (dash lines). Scale bar: 5μm. (c) Quantification of data in (b) showing the number of H3K9^me3 foci/H3K9^me3-positive neuron. H3K9^me3-negative neurons were excluded from the analysis. Quantification of the number of H3K9^me3-negative neurons, which were not found in aged controls. 6 full-fields at 630 magnification/sample were counted. Values are mean ± SEM. *P < 0.05; (**) < 0.01; Student’s t-test. (d) Immunoblot using extracts from the frontal cortex of age-match control and AD patients. (d’) Quantification of the results showed in (d). (e) Immunoblot using extracts from the hippocampus of age-match control and FAD patients. (f) IHC staining for p-ATM on paraffin sections from the frontal cortex of age-match control (n = 2) and AD (n = 2) patients. p-ATM is predominant in AD neurons and accumulates in both cytosolic (blue arrowhead) and nuclear (black arrowhead) compartments. (g) ChIP experiments were performed on frontal cortex extracts of age-match control (n = 6) and AD brains (n = 6). All data are represented as fold of input. (A) Note BMI1 and H3K9^me3 enrichment at McBOX, SATIII and SATA in control samples. BMI1 was also found at HOXC13. BMI1 and H3K9^me3 were depleted at all loci in AD samples (bottom). Fold differences between control and AD samples for p-ATM, p-ATR and γH2AX accumulation. Values are mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; Two way-ANOVA test was performed for multiple gene analysis and Student’s t-test for single gene analysis.