Introduction

This article will describe the use of epigenetics in improving Alzheimer’s disease degeneration. The first part of the article will introduce the epidemiology of Alzheimer’s Disease (AD), a definition of epigenetics, and a description of the epigenetics development in AD. The second part of the article will discuss epigenetic modifications that may combat AD degeneration.

The Importance of studying Alzheimer’s Disease

AD is one of the world’s central major neurodegenerative diseases, which is usually presented with memory loss, dementia, and progressive cognitive dysfunction [1]. It negatively affects people’s lives and demonstrates a heavy economic and social burden. According to recent estimates, 44 million individuals worldwide currently suffer from dementia [1]. Up to 2019, the total cost of care for people with dementia in the UK is £34.7 billion. According to estimates, 1.6 million people will have dementia in 2040 [2]. The most common cause of dementia, accounting for 50% to 75% of cases, AD is essentially a disorder of aging, with prevalence almost doubling every five years after age 65. Additionally, the World Health Organization identified AD as a public health concern and priority. Although nowadays, AD-modifying treatments are not available, a focus on the epigenetic mechanism of AD is being explored.

The Role of Epigenetics in patients suffering from Alzheimer’s Disease

Epigenetics means the control of genome expression above the change and beyond genetics. It includes DNA methylation, histone modification, and noncoding RNA molecules [3]. Epigenetics varies with age, and age acceleration is known to be associated with AD risk factors such as BMI, smoking, and obesity [4]. These connections can be easily explained. For example, the DNA methylation in AD can lead to the formation of the 5-methylcytosine (5-mC) and hydroxyl methylcytosine (5-hmC) in CpG dinucleotide clusters, which are known as the CpG islands [5]. These can repress the expression of proteins involved in neuronal inflammation and lipid metabolism associated with the synthesis of amyloid-β peptide (Aβ) peptide. These processes are vital critical points involved in obesity and hypertension in turn, which may be related to the early onset of Alzheimer’s disease [6].

Scientists and researchers generated epigenome-wide methylation and hydroxymethylation studies (EWAS) to collect the patients and samples for analysis and set up randomized controlled trials. Culture cells in vitro and in vivo to suspect the new biomarkers could predict the early onset of Alzheimer’s disease more accurately [7]. Otherwise, the random loci of the methylation and histone modifications can be conflicted. The desire to collect blood samples and CSF is also necessary for more broadly discovering biomarkers. The isolation of Lewy bodies that may be presented in Alzheimer’s disease is essential, too, to tell the distinguishes [8].

How epigenetics modifications can improve Alzheimer Disease degeneration.
The second part of the article will be focused on how epigenetics modifications can improve AD degeneration. Epigenetics oversees gene expressions with gene nucleotide sequences that don’t change but with other modification components such as histone acetylation and DNA methylation that change. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are enzymes that catalyze the acetylation and deacetylation of histones, respectively. HDAC inhibitors are the most widely studied therapy of AD in epigenetics treatment. They were previously used as anticancer drugs, but recently it has been proposed that HDAC can work as neuroprotectors by improving synaptic plasticity, learning, and memory. They are helpful for cognition improvement and memory recovery [10].

As per DNA methylation and as mentioned in the first part, it has already been proved that DNA methylation affects AD. The target of non-coding RNA epigenetics for therapy is based on the anti-microRNA and precursor analogs, which are molecular genetic aspects [12]. MicroRNA or miRNA are 18-25 nucleotides in length that influence gene expression. They modify the AD’s risk and/or progression by directly affecting and targeting amyloid precursor protein (APP) and β-site APP cleaving enzyme (BACE1).

Although there is hope for the future, in both the pharmacological way and gene editing therapies, the most significant challenges are the low permeability of the blood-brain barrier, which allows low concentration permeability that could not be effective [13].

Conclusion

In conclusion, AD is identified as a priority concern for public health, therefore, it is important to find AD-modifying treatments. Epigenetics seems like a promising area in improving AD. It includes DNA methylation, histone modification, and noncoding RNA molecules, which also offer a way to improve AD degeneration.

The article is written by Jenny Zhang, Nanchang University, China

References

1. Lane, C.A., J. Hardy, and J.M. Schott, Alzheimer’s disease. Eur J Neurol, 2018. 25(1): p. 59-70.
2. What are the costs of dementia care in the UK? ; Available from: https://www.alzheimers.org.uk/about-us/policy-and-influencing/dementia-scale-impact-numbers.
3. Lardenoije, R., et al., Neuroepigenetics of Aging and Age-Related Neurodegenerative Disorders. Prog Mol Biol Transl Sci, 2018. 158: p. 49-82.
4. McCartney, D.L., et al., Investigating the relationship between DNA methylation age acceleration and risk factors for Alzheimer’s disease. Alzheimers Dement (Amst), 2018. 10: p. 429-437.
5. Christopher, M.A., S.M. Kyle, and D.J. Katz, Neuroepigenetic mechanisms in disease. Epigenetics Chromatin, 2017. 10(1): p. 47.
6. Sharma, V.K., V. Mehta, and T.G. Singh, Alzheimer’s Disorder: Epigenetic Connection and Associated Risk Factors. Curr Neuropharmacol, 2020. 18(8): p. 740-753.
7. Smith, A.R., G. Wheildon, and K. Lunnon, Invited Review – A 5-year update on epigenome-wide association studies of DNA modifications in Alzheimer’s disease: progress, practicalities and promise. Neuropathol Appl Neurobiol, 2020. 46(7): p. 641-653.
8. Verberk, I.M.W., et al., Characterization of pre-analytical sample handling effects on a panel of Alzheimer’s disease-related blood-based biomarkers: Results from the Standardization of Alzheimer’s Blood Biomarkers (SABB) working group. Alzheimers Dement, 2022. 18(8): p. 1484-1497.
9. Sanchez-Mut, J. and J. Gräff, Epigenetic Alterations in Alzheimer’s Disease. Frontiers in behavioral neuroscience, 2016. 9: p. 347.
10. Yang, S.S., et al., The development prospection of HDAC inhibitors as a potential therapeutic direction in Alzheimer’s disease. Transl Neurodegener, 2017. 6: p. 19.
11. Li, A., Z. Koch, and T. Ideker, Epigenetic aging: Biological age prediction and informing a mechanistic theory of aging. J Intern Med, 2022.
12. Takousis, P., et al., Differential expression of microRNAs in Alzheimer’s disease brain, blood, and cerebrospinal fluid. Alzheimers Dement, 2019. 15(11): p. 1468-1477.
13. Rezai, A.R., et al., Noninvasive hippocampal blood-brain barrier opening in Alzheimer’s disease with focused ultrasound. Proc Natl Acad Sci U S A, 2020. 117(17): p. 9180-9182.