The recent FDA approval of Donanemab has sparked celebration within the Alzheimer’s research community, offering significant hope by slowing cognitive decline in some patients. However, it is clear to scientists that Donanemab is not a cure, and the quest to truly halt or reverse Alzheimer’s disease (AD) remains ongoing.
Donanemab works by targeting amyloid beta (Aβ) plaques, a hallmark protein buildup in AD’s pathology. While clearing these plaques marks a critical step, it may not address the root cause of the disease. This is where the study of epigenetics helps, providing insights into how gene expression is regulated without altering the DNA sequence.
Alzheimer’s is a progressive neurodegenerative disease marked by memory loss and cognitive decline. Pathologically, it involves the buildup of Aβ plaques and tau protein tangles, along with other dementia-related features like Lewy bodies and TDP-43 pathology (McAleese et al., 2017). AD disrupts many functions within brain cells, affecting protein handling, communication, and overall health. These disruptions likely stem from a complex interplay of genetics, biology, and environment. Research suggests abnormal epigenetic patterns might be involved in AD.
By studying mechanisms like DNA methylation, histone modification, and RNA methylation, researchers aim to uncover new ways to influence the production of proteins involved in AD, potentially leading to more effective treatments.
DNA Methylation
DNA methylation and hydroxymethylation are fundamental processes implicated in AD. DNA methylation involves the addition of a methyl group (5mC) to DNA, which typically results in gene silencing and can profoundly impact brain function. In contrast, hydroxymethylation (5hmC) is associated with gene activation, particularly in brain tissues. These processes play crucial roles in regulating the expression of genes involved in memory formation and neuronal function, processes that are severely affected in AD pathology.
Patterns of DNA methylation and hydroxymethylation undergo significant changes in AD. These alterations are closely linked to the development of AD-related pathologies, including the accumulation of Aβ plaques and tau protein tangles, which are hallmark features of the disease. Specific studies have highlighted increased DNA methylation at precise locations within the Hox gene cluster, showing a correlation with AD pathology (Smith et al., 2018). Moreover, changes in methylation levels in genes such as ABCA7, BIN1, SORL1, and SLC24A4 have been associated with variations in Aβ accumulation and tau protein entanglement, further underlining the significance of epigenetic mechanisms in AD progression (Yu et al., 2015).
Biomarkers of aging, such as Horvath’s and Hannum’s clocks, utilize DNA methylation patterns to assess biological aging and have been linked to AD features like plaque formation and cognitive decline (Bergsma et al., 2020). Exploring these biomarkers provides valuable insights into the physiological changes associated with healthy aging and cognitive functions, offering potential avenues for early diagnosis and intervention in AD.
Histone Modification
In eukaryotic cells, nuclear DNA is wrapped around histones and organized into chromatin. Modifications to both histones and DNA can affect chromatin remodeling and regulate gene expression. Histones have been shown to be cytotoxic and can trigger cell death and inhibit gene expression by preventing transcription factors from binding to promoters, suggesting histones may have adverse effects on gene expression. Histone posttranslational modifications, or epigenetic markers like methylation, acetylation, and phosphorylation, can impact gene expression by altering the structure of chromatin. These modifications are closely linked to AD pathology, including abnormal tau phosphorylation and Aβ protein plaques.
Histone methylation, involving methyl group addition to histones, alters chromatin structure and influences gene expression, replication, and repair. Specific patterns, like trimethylation of histone H3 at lysine 4 (H3K4me3), are associated with memory-related genes and synaptic function, impacting AD progression. Dysregulation of histone methylation is observed in aging and neurodegenerative diseases, including AD. For instance, increased levels of the repressive modification H3K9me2 in the prefrontal cortex of familial AD (FAD) mouse models and patients correlate with higher EHMT1 expression. In FAD models, this alteration is linked to reduced AMPA and NMDA receptor subunits, and treatment with EHMT1/2 inhibitors reversed these changes, indicating potential for targeting histone methylation in AD therapy (Santana et al., 2023).
Histone acetylation, catalyzed by enzymes like histone acetyltransferases (HATs), also affects chromatin structure. Acetylation generally promotes gene expression and is crucial for learning and memory-related genes. Dysregulation of acetylation, such as increased levels of histone deacetylases (HDACs), is observed in AD. Inhibitors of HDACs, like HDAC6, can increase histone acetylation, enhancing memory-related gene expression and potentially delaying AD progression. Conversely, increased HDAC levels are associated with cognitive decline and Aβ protein deposition in AD. (Lu et al., 2015)
RNA Methylation
RNA methylation, particularly m6A modification, plays a critical role in AD, influencing gene expression by modulating mRNA stability and translation. (Xia et al., 2023) Reduced m6A modification in AD brains is associated with synaptic loss, neuronal atrophy, and gliosis, contributing to memory impairment and dementia. Changes in m6A methylation during brain development are spatially specific and dynamic, with dysregulation implicated in the progression from mild cognitive impairment to AD. (Shafik et al., 2021)
Additionally, modifications of non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been found to play a role in regulating gene networks involved in memory, learning (synaptic plasticity), and inflammation in the brain. Abnormal patterns in these ncRNAs could contribute to the development and progression of AD. Thus, variations in these modifications could potentially serve as biomarkers or therapeutic targets for diagnosing and treating AD. (Olufunmilayo et al., 2023)
Furthermore, RNA methylation dysregulation impacts oligodendrocyte function and myelination, leading to white matter abnormalities observed in AD brains. (Zhou et al., 2022) APOE, a key genetic risk factor for AD, may interact with m6A methylation regulators, adding another layer to the complex relationship between RNA methylation and AD. Understanding the role of m6A modification in non-coding RNAs and coding RNAs provides insights into AD mechanisms and identifies potential therapeutic targets for intervention.
Epigenetic Insights and Future Directions
Epigenetic studies hold significant importance in AD research, especially given the limitations of current therapeutic approaches. While genetics contribute to some cases, many lack a clear genetic basis. Epigenetics explores how genes are expressed and how environmental and lifestyle factors can alter gene activity without modifying the DNA sequence. Understanding these mechanisms could unveil novel therapeutic targets that modify gene expression, offering potential avenues to slow or prevent AD – a promising direction in a field currently hindered by limited treatment options.
References:
- McAleese KE, et al. 2017. TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies, and aging. Brain Path.
- Smith RG, et al. 2018 Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer’s disease neuropathology. Alzheimer’s Dement.
- Yu L, et al. 2015. Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer’s disease. JAMA Neurol.
- Bergsma T, et al. 2020. DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan. Neurosci Insights.
- Santana DA, et al. 2023. Histone Modifications in Alzheimer’s Disease. Genes (Basel).
- Lu X, et al. 2015. Histone Acetylation Modifiers in the Pathogenesis of Alzheimer’s Disease. Front Cell Neurosci.
- Xia L, et al. A new perspective on Alzheimer’s disease: m6A modification. Front Genet.
- Shafik AM, et al. 2021. N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer’s disease. Genome Biol.
- Olufunmilayo EO, et al. 2023. Roles of Non-Coding RNA in Alzheimer’s Disease Pathophysiology. Int J Mol Sci.
- Zhou J, et al. 2022. White Matter Damage in Alzheimer’s Disease: Contribution of Oligodendrocytes. Curr Alzheimer Res.
