Epigenetic mechanisms play tremendous roles in the development and management of neural processing. The important mechanisms include inactivation of transcription via methylation, histone modification via acetylation/deacetylation, and miRNA regulation. These modifications allow for expression or silencing of genes, without manipulation of nucleotide sequence. An individual's internal and external environments provide input for quotidian epigenetic regulation. Aberrations in the form of regulation have been increasingly linked to neurological disorders, in addition to the established correlation to tumorigenesis. In recent years, deviations from normal epigenetic patterns have been observed in cases of Alzheimer's disease (AD). The brains of patients with AD have been shown to display significantly less methylation overall, as compared to age-matched controls. Of particular concern, the methylation, which normally keeps the promoter of the APP gene silenced, occur far less frequently in AD patient allowing for the progression of amyloid deposition and subsequent tau pathology. In addition to the hypomethylation present in AD, many AD cases present with a concurrent hypoacetylation on histones in the hippocampus. There is strong evidence suggesting that the reduced levels of acetylation are due to over-activation of histone deacetylases. Post-mortem examinations of the brains of AD patients have shown that the brain-derived neurotrophic gene, which is crucial for neural processing associated with maturation and memory, has low levels of acetylation halting its transcription. While low levels of methylation and acetylation seem to contribute to the pathogenesis of AD, regulatory miRNA levels can have adverse effects whether they are aberrantly reduced or increased. Patients with AD tend to show abnormally augmented expression of miRNA-125b, miRNA-128, and miRNA-9 in the hippocampus, while a reduced expression of miRNA-107. Deregulation of these miRNAs have been linked to the progression of AD and include amyloid deposition, tau pathology, and oxidative stress through inflammatory processes. The latter quandary of oxidative stress has been shown to be crucial for the early progression of AD. Reactive oxygen species disallow the methylation of genes due to steric hindrance at the CpG islands of DNA where DNA methyltransferases act. Research shows that increases in oxidative stress are correlated to decreases in methylation, which allows for APP expression. While these alterations to normal epigenetic patterns occur internally, there is a breadth of changes that the external environment imposes to exacerbated AD pathogenesis. Most heavily studied of these external environmental factors is lead exposure. There is a strong correlation between lead exposure in individuals who carry the ApoE4 gene and increased mRNA transcription of the APP gene. Lead is thought to demethylate the promoter of the APP gene and allow for amyloid processes to occur. Inadequate nutrition, specifically deficits in choline and folate, has been linked to hypomethylated states due to an inefficient "methylation/remethylation cycle" leading to an accumulation of homocysteine characteristic of AD.
With the emphasis epigenetic deregulation has in the progression of AD, epigenetic treatments need to be seriously considered as therapeutic avenues. Current drugs treat the symptoms and acute conditions of AD, but through epigenetic modifications, the pathology of the diseases can be directly addressed. Potential therapeutic avenues include the use of methyl donors, highly specific histone deacetylase inhibitors, and miRNA biomarkers. Methyl donors can help alleviate the hypomethylated state and prevent further APP expression and amyloid deposition. Currently, the histone deacetylase inhibitors are being used as global inhibitors, but have adverse effects including non-specific and premature cell death. By further researching these inhibitors and finding a mechanism to attack specific histone deacetylases (such as HDAC6 in AD), the efficacy of this aspect of treatment will be greatly increased.
The current use of miRNAs as epigenetic regulators to turn off unwanted genetic expression is ineffective due to a major problem of effective delivery to target zones. By using the gene sequences of miRNAs as biomarkers, an AD patient's genomic sequence can be mapped, marking which areas require regulation. This process is necessary because of the inter-individuality of miRNA regulation between each case of AD. Also, the problem of some anti-miRNA molecules not being able to cross the blood brain barrier needs to be addressed using a novel transport mechanism, as direct brain injections are not feasible. The simplest, and highly effective, therapeutic avenue is a healthy lifestyle. Daily exercise and proper nutrition hinder inflammatory process and oxidative stress and can prevent progression of AD through allowing higher brain perfusion for cognitive functioning.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/14336 |
| Date | 22 January 2016 |
| Creators | Nitta, Vishnukartik |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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