Epigenetic modifications in frontal cortex from Alzheimer's disease and bipolar disorder patients

J S Rao, V L Keleshian, S Klein, S I Rapoport, J S Rao, V L Keleshian, S Klein, S I Rapoport

Abstract

Alzheimer's disease (AD) and bipolar disorder (BD) are progressive brain disorders. Upregulated mRNA and protein levels of neuroinflammatory and arachidonic acid (AA) markers with loss of synaptic markers (synaptophysin and drebrin) have been reported in brain tissue from AD and BD patients. We hypothesized that some of these changes are associated with epigenetic modifications of relevant genes. To test this, we measured gene-specific CpG methylation, global DNA methylation and histone modifications in postmortem frontal cortex from BD (n=10) and AD (n=10) patients and respective age-matched controls (10 per group). AD and BD brains showed several epigenetic similarities, including global DNA hypermethylation, and histone H3 phosphorylation. These changes were associated with hypo- and hypermethylation of CpG islands in cyclooxygenase-2 and brain-derived neurotrophic factor promoter regions, respectively. Only the AD brain showed hyper- and hypomethylated CpG islands in promoter regions for cAMP response element-binding protein and nuclear transcription factor kappa B genes, respectively. Only the BD brain demonstrated increased global histone H3 acetylation and hypermethylation of the promotor region for the drebrin-like protein gene. There was no significant epigenetic modification for 12-lipooxygenase or p450 epoxygenase in either illness. Many observed epigenetic changes were inversely related to respective changes in mRNA and protein levels. These epigenetic modifications involving neuroinflammatory, AA cascade and synaptic markers may contribute to progression in AD and BD and identify new targets for drug development.

Figures

Figure 1
Figure 1
Mean levels of CpG methylation at promoter region of cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LOX) and p450 epoxygenase in frontal cortex of Alzheimer's disease (AD) (a, c, e) and bipolar disorder (BD) patients (b, d, f). Mean levels of brain-derived neurotrophic factor (BDNF) mRNA in AD and control brain samples (g). Mean±s.e.m. (n=10 per group). *P<0.05, **P<0.01, ***P<0.001.
Figure 2
Figure 2
Mean CpG methylation at promoter region of brain-derived neurotrophic factor (BDNF), cAMP response element-binding (CREB) factor, synaptophysin and drebrin-like protein in frontal cortex of Alzheimer's disease (AD) (a, c, e, g) and bipolar disorder (BD) (b, d, f, h) patients and respective controls. Mean±s.e.m. (n=10 per group). *P<0.05, **P<0.01, ***P<0.001.
Figure 3
Figure 3
Mean CpG methylation at promoter region of nuclear transcription factor kappa B (NF-κB) in frontal cortex of Alzheimer's disease (AD) (a) and bipolar disorder (BD) (b) patients and respective controls. Relative expression of NF-κB p50 and p65 mRNA levels in AD (c). Mean levels of global DNA methylation, global histone H3 phosphorylation and global histone H3 acetylation in frontal cortex of AD (d, f, h) and BD patients (e, g, i) and controls. Mean±s.e.m. (n=10 per group). *P<0.05, **P<0.01, ***P<0.001.

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