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.
Highlights
Alzheimer’s disease (AD) and bipolar disorder (BD) are progressive neuropsychiatric illnesses with overlapping symptoms and neuropathology, including brain atrophy, cognitive impairment, emotional disturbances, neuroinflammation, excitotoxicity and upregulated brain arachidonic acid (AA) metabolism.[1,2,3] Common behavioral disturbances in AD, aside from memory loss, are apathy, depression, agitation and general withdrawal
We studied frontal cortex because functional and structural abnormalities have been reported in this region in AD31–36 and BD patients, and we had studied in previously.[37,38,39,40,41,42]
Hypomethylated COX-2 promoter region in AD and BD. Both AD and BD compared with respective control frontal cortex (Brodmann area 9) show increased AA cascade markers.[1,3]
Summary
Alzheimer’s disease (AD) and bipolar disorder (BD) are progressive neuropsychiatric illnesses with overlapping symptoms and neuropathology, including brain atrophy, cognitive impairment, emotional disturbances, neuroinflammation, excitotoxicity and upregulated brain arachidonic acid (AA) metabolism.[1,2,3] Common behavioral disturbances in AD, aside from memory loss, are apathy, depression, agitation and general withdrawal. Several studies have implicated epigenetic mechanisms in these illnesses.[12,13] In this study, we examined brain epigenetic changes in AD and BD
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