Epigenetics of Alzheimer’s Disease

By Lubova Dziojeva 

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting approximately 50 million people worldwide (Alzheimer’s Association, 2019). The features associated with Alzheimer’s include neuroinflammation, accumulation of insoluble amyloid beta (Aβ) filaments (formed from cleavage of amyloid precursor protein, APP) and formation of intracellular neurofibrillary tangles of hyperphosphorylated tau protein (Selkoe, 2012). AD causes neurodegeneration in a range of brain regions, such as the cerebral cortex, hippocampus, and amygdala (Mrdjen et al., 2019)The impacted areas are associated with different stages of Braak progression.  

Only an estimated 1-6% of AD is caused by genetic mutations associated with early onset AD (Bekris, Yu, Bird, & Tsuang, 2010). The rest of the cases are not genetic and are called sporadic or late onset. One of the first indications of an involvement of an epigenetic mechanism in AD came from a study on monozygotic twins discordant for Alzheimer’s. A significant reduction in methylation in the neocortex was observed in the twin with AD  (Mastroeni, McKee, Grover, Rogers, & Coleman, 2009). Following this study several other hyper- and hypo-methylation patterns have been detected in neuronal and glial cells. Meta-analysis has been employed by several studies to identify epigenetic changes in a larger sample size. This has led to the identification of significant methylation changes in several genes: HOX3A, APP, SEC14L1, MCF2L, and LRRC8B (Gasparoni et al., 2018). The HOXA gene cluster coordinates neuronal development and organisation of neuronal circuits. Epigenetic dysregulation has also been demonstrated in diseases such as Parkinson’s and Huntington’s. MCF2l encodes a protein which forms part of the signalling pathway used to regulate formation and stabilisation of glutamatergic synapses of cortical neurones. SEC14L1 codes for a protein involved in vesicular trafficking of acetylcholine (ACh). LRRC8B encode anion channels that transport neurotransmitters glutamate, aspartate, gamma-aminobutyric acid (GABA) (Gasparoni et al., 2018). In the adult brain, glutamate and aspartate acts as excitatory neurotransmitters balanced by the inhibitory action of GABA (Wu & Sun, 2015). 

Aβ protein is formed from amyloid precursor protein or APP. Studies have shown methylation changes at the APP gene in individual AD cases, while larger studies could not confirm this observation. Methylation changes for APP were not detected in the bulk brain tissue samples nor reported from tissue screens. Heterogeneity of tissue composition is a common cause of noise in epigenetic profiles. Thus, separating cells into neuronal and glia cell types allowed a group of researchers to find the previously undetected methylation changes at the APP locus (Gasparoni et al., 2018). The methylation site was found at the promoter overlapping with a confirmed CTCF transcription factor binding region indicating a gain of sensitivity for pre-sorted samples. This region has been shown to regulate APP transcription. The data suggest that during AD progressive loss of DNA methylation at this region results in enhanced binding of CTCF transcription factor thus increasing APP transcription (Gasparoni et al., 2018). This sensitivity of this experiment could be enhanced further if the neurone and glia cells were separated into sub-populations (eg. glutamatergic, GABAergic, dopaminergic neurones and microglia, astrocytes) potentially leading to detection of cell-type specific epigenetic changes during AD progression as well as resistant cell types. 

Chromatin can also be dynamically altered by changes in methylation patterns. Neurone specific overexpression of histone deacetylase 2 (HDAC2) was shown to lead to decreased level of synaptic plasticity, memory, learning and number of synaptic connections (Guan et al., 2009). This has implications for potential treatments of the memory loss and cognitive decline associated with AD in the form of HDAC inhibitors.

The Aβ pathway has been a major focus of the field due to several lines of evidence suggesting its central role in the toxicity of AD  (Butterfield et al., 1997). However, determination of Aβ-independent pathways such as the implicated pathways uncovered through epigenome studies would allow for the detection of more drug targets for intervention.   

ADis thought to arise 20 or more years before the affected individual first experiences symptoms (Alzheimer’s Association, 2019). Therefore, early diagnosis is crucial to halt disease progression. Epigenome-wide association studies represent one way of applying genome-wide assays to identify molecular events that could be associated with human phenotypes. The epigenome is an attractive target for mediating disease risk by modifying the extracellular stimuli. The importance of the highlighted research is for development of stable biomarkers that could help identify the onset of disease earlier, uncover more about the mechanisms that underly AD development and allow for interventions prior to the onset of cognitive and behavioural changes.  Treatments based on inhibition of DNA methyltransferases and HDACs cannot cross the blood brain barrier, as well as having to first be modified to prevent off-target effects and reduce genotoxicity, a significant challenge to this approach. Another factor under investigation is the disproportionate effect of AD on women, where epigenetics may offer a new perspective to determine whether the higher longevity of women is the only contributing factor (Snyder et al., 2016).  Even though, the suggestion of the role of epigenetic impairment in AD is a relatively recent one, the growing volume of research is confirming the importance of this connection. 

References:

Alzheimer’s Association. (2019). 2019 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 15(3), 321-387.

Bekris, L. M., Yu, C., Bird, T. D., & Tsuang, D. W. (2010). Genetics of Alzheimer disease. Journal of Geriatric Psychiatry and Neurology, 23(4), 213-227.

Butterfield, D. A. (1997). Β-amyloid-associated free radical oxidative stress and neurotoxicity: Implications for Alzheimer’s disease. Chemical Research in Toxicology, 10(5), 495-506.

Gasparoni, G., Bultmann, S., Lutsik, P., Kraus, T. F., Sordon, S., Vlcek, J., et al. (2018). DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex. Epigenetics & Chromatin, 11(1), 41.

Guan, J., Haggarty, S. J., Giacometti, E., Dannenberg, J., Joseph, N., Gao, J., et al. (2009). HDAC2 negatively regulates memory formation and synaptic plasticity. Nature, 459(7243), 55-60.

Mastroeni, D., McKee, A., Grover, A., Rogers, J., & Coleman, P. D. (2009). Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PloS One, 4(8), e6617.

Mrdjen, D., Fox, E. J., Bukhari, S. A., Montine, K. S., Bendall, S. C., & Montine, T. J. (2019). The basis of cellular and regional vulnerability in Alzheimer’s disease. Acta Neuropathologica, , 1-21.

Selkoe, D. J. (2012). Preventing Alzheimer’s disease. Science, 337(6101), 1488-1492.

Snyder, H. M., Asthana, S., Bain, L., Brinton, R., Craft, S., Dubal, D. B., et al. (2016). Sex biology contributions to vulnerability to Alzheimer’s disease: A think tank convened by the women’s Alzheimer’s research initiative. Alzheimer’s & Dementia, 12(11), 1186-1196.

Wu, C., & Sun, D. (2015). GABA receptors in brain development, function, and injury. Metabolic Brain Disease, 30(2), 367-379.

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