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Murai, T.; Matsuda, S. Epigenetics and Alzheimer’s Disease and Parkinson’s Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/48849 (accessed on 08 September 2024).
Murai T, Matsuda S. Epigenetics and Alzheimer’s Disease and Parkinson’s Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/48849. Accessed September 08, 2024.
Murai, Toshiyuki, Satoru Matsuda. "Epigenetics and Alzheimer’s Disease and Parkinson’s Disease" Encyclopedia, https://encyclopedia.pub/entry/48849 (accessed September 08, 2024).
Murai, T., & Matsuda, S. (2023, September 05). Epigenetics and Alzheimer’s Disease and Parkinson’s Disease. In Encyclopedia. https://encyclopedia.pub/entry/48849
Murai, Toshiyuki and Satoru Matsuda. "Epigenetics and Alzheimer’s Disease and Parkinson’s Disease." Encyclopedia. Web. 05 September, 2023.
Epigenetics and Alzheimer’s Disease and Parkinson’s Disease
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This entry is adapted from the peer-reviewed paper 10.3390/epigenomes7030020

Chronic neurodegenerative disorders are believed to be caused by a combination of multiple events that damage neuronal function. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and Parkinson’s disease (PD) is the second-most common neurodegenerative disorder worldwide. Epigenetics is defined as the stable inheritance of a phenotype, resulting from changes in the chromosomal DNA without mutations in the nucleotide sequence. A number of epigenetic research has revealed that the modification of histones accompanied by both a local and global remodeling of the chromatin structure and alternations in the transcriptional patterns are closely associated with the pathogenesis of neurodegenerative diseases, including AD and PD. 

Alzheimer’s disease Parkinson’s disease phytochemicals dietary intervention epigenetics transcriptome epigenome

1. Epigenetics and Alzheimer’s Disease

Alzheimer’s disease (AD) is a common type of neurodegenerative disorder, the typical diagnostic phenotypes of which are the enhanced deposition of senile plaques composed of insoluble, neurofibrillary proteins in the brain. These aggregates mainly consist of an early accumulation amyloid-β (Aβ) protein with an abnormal form of aggregation and hyperphosphorylated tau proteins in the hippocampus that eventually lead to cognitive impairment over time [1]. The established biomarkers used at present are Aβ1–42, total-tau, and phosphorylated-tau in the cerebrospinal fluid (CSF). Actual therapeutic and pharmacological interventions effective in the management of AD that impede the progress of the disease have not been developed, with the only intervention being restricted to symptomatic treatments that retard the progress of the disease [2]. Therefore, the establishment of new methods effective in treating AD and the unraveling of the neurodegenerative mechanism is of significance for biomedical researchers [3]. Although the stage of the disease and the mechanism by which neurodegeneration occurs during the pathogenesis of AD have remained unresolved, many trials have been performed to clarify the pathophysiological features of neuroinflammation in AD based on the multiple parameters concerning inflammatory mediators [4]. Additionally, oxidative stress may contribute to the progression and pathogenesis of AD [5]. Oxidative stress induced in the neuronal cells was mainly attributed to the excess production of reactive oxygen species (ROS), which plays a key role in the progression of AD [6]. ROS refers to a family of ionic species continuously generated from O2 and scavenged within the cells. The major ROS include H2O2 (hydrogen peroxide), O3 (ozone), O2−•(superoxide anion radical), and OH• (hydroxyl radical) [4]. Dysregulation of ROS contributed to the pathogenesis of neurodegenerative diseases [7]. An increased ROS production adversely affected DNA function, including its epigenetic modification related to AD [8]. In fact, an accumulating body of evidence implied that oxidative stress is the main AD risk factor by inducing the apoptosis of neurons and dysfunction of the brain at the initiation stage and throughout AD progression [9]. It is also of note that the DNA of hyper-methylated nucleotides was easily influenced by β-amyloid-promoted oxidative damage as methyl-cytosines restricted the repair of the adjacent hydroxy-guanosines [10].

2. Epigenetics and Parkinson’s Disease

Parkinson’s disease (PD) is a prevalent neurodegenerative disease with the characteristics of neuropsychiatric symptoms, including depression and anxiety, existing before the onset of symptoms related to motor and movement illnesses [11]. Most patients clinically present with motor disorder and suffer from slowness of movement, rest tremors, rigidity, and disturbances in balance; the major pathophysiological features include the substantia nigra (SN)’s dopaminergic neuron loss and Lewy body depositions [11]. The dysfunction of mitochondria, which results in oxidative stress, may cause the progression of PD [12]. The dopaminergic neuron activities in the SN is critical for striatal synaptic plasticity and positive learning, and their degeneration led to an initiation of the subthalamic nucleus, that in turn amplified the excitation signals relayed to the SN [13]. Exposure to harmful mediators in the environment, such as ROS, might cause the initiation of neurodegeneration with clinical symptoms similar to those of PD [14]. Therefore, it is necessary to establish methods for ensuring the longevity of healthy neurons following an attack by ROS without using specific medications. A close association between genetics and environmental factors may determine the fate of PD, and the participation of many networks involving DNA, proteins, organelles, and neural networks may contribute to the complexity in the manifestation of symptoms [15]. Many pathogenesis-related associations have been focused on for the management of symptoms and progression of PD [15]. While dopaminergic-based treatments have been the gold standard for the symptomatic control of PD, a few requirements for the management of dopaminergic-resistant motor/non-motor symptoms remain unaddressed and for treatments altering the normal clinical course of PD [15].
Recently, much effort has been made for elucidating the epigenetics driving the alternations of gene expression associated with the pathogenesis of PD. The alternations in gene expression are a well-known cause of PD, and epigenetics is likely to play a critical role in its regulation [16]. Epigenetic regulatory mechanisms surrounding the SNCA gene, which encodes the α-synuclein (α-syn) protein, are suggested in [16]. A genome-wide epigenome study in the frontal cortex and in the blood of PD patients revealed that more than 80% of differentially methylated sites identified were hypomethylated in PD cases [16]. Among the top hits of PD hypermethylated genes was microtubule-associated protein tau (MAPT), which encodes the tau protein [16]. Therefore, an imbalanced epigenetic alternation may cause harmful effects. Environments may raise an objection for the formation and maintenance of epigenetics and may thereby fill a gap between the deeper understanding of the origin and pathogenesis of neurodegenerative diseases [17]. A recent study on genome-wide DNA methylation in brain and blood samples of PD patients revealed a characteristic methylated pattern involving a number of genes implicated in PD; thus, the functional significance of epigenetics as a regulatory factor in PD is evident, implying that peripheral blood may be a promising source for detecting DNA methylation levels in addition to brain tissue for the discovery of biomarkers associated with PD [18]. Given that PD is a disease with many related disorders—including a variety of clinical symptoms—epigenetic regulation, treatment response, and survival may possibly reflect multimodal changes, i.e., genetic, epigenetic, proteinaceous, and organellar contributions; thus, substantial improvement on diagnostic procedures may improve the success of therapeutic methods, the mechanisms of action of which may be beneficial for PD patients [19].

3. Dietary Approaches for the Management of Neurodegeneration

The mutual relation between diet/nutrition and the immune system plays an important role in the maintenance of the human body. A systematic determination of the full range/variety of cells has been a challenge due to limitations of analytical methods that have restricted the parameters that can be determined. Recently, the single-cell techniques have overwhelmed these limitations with their high-throughput properties [20]. The interactions also contribute to the progression of diseases, including neurodegenerative diseases. Therefore, along with these large international projects, a healthcare-based approach integrating single-cell techniques may offer deeper insights into the current state of studies on nutritional and molecular medicine and serve to discover and develop new clinical interventions for the treatments of diseases shortly [21].
Accumulating evidence suggests that a variety of dietary plant phytochemicals exhibit neuroprotective effects. For example, resveratrol improved overall cognitive performance in postmenopausal women [22]. Another randomized phase II trial of resveratrol in individuals with mild to moderate AD revealed that Aβ40 in CSF and plasma Aβ40 levels declined more in the placebo group than the resveratrol-treated group [23]. Resveratrol supplementation prevents cognitive decline by restoring the epigenetic landscape as well as synaptic plasticity [24]. Anthocyanin, richly present in blueberry, inhibited Aβ fibrillation and a reduced ROS production in microglial cells [25]. Hydroxytyrosol found in diverse vegetable species exhibited an antioxidant effect in a PD model [26]. Ginsenoside and paeoniflorin decreased α-syn fibrillation and accumulation, respectively [27][28] (Table 1). A variety of other dietary compounds possess neuroprotective properties, and may act on several cellular targets to prevent the development of PD or to attenuate the progress of the disease [29]. Notably, many clinical and pre-clinical studies have reported protective effects of certain dietary micronutrients for PD [29]. The candidate micronutrients for therapeutic use in PD have been summarized in the literature [29]. Further well-designed clinical studies are needed to evaluate the therapeutic benefits of these dietary phytochemicals as promising agents in the management of PD.
Table 1. The potential effects of dietary phytochemicals in neurodegenerative diseases.
Phytochemicals Effects References
Resveratrol Enhance cognition [22]
Resveratrol Decrease in Aβ level [23]
Resveratrol Epigenetics [24]
Anthocyanin Inhibit Aβ fibrillation [25]
Hydroxytyrosol Antioxidant effect in PD [26]
Ginsenoside Decrease in α-syn fibrillation [27]
Paeoniflorin Decrease in α-syn accumulation [28]

References

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  4. Murai, T.; Matsuda, S. Therapeutic implications of probiotics in the gut microbe-modulated neuroinflammation and progression of Alzheimer’s disease. Life 2023, 13, 1466.
  5. Halliwell, B. Oxidative stress and neurodegeneration: Where are we now? J. Neurochem. 2006, 97, 1634–1658.
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  7. Murai, T.; Matsuda, S. Pleiotropic signaling by reactive oxygen species concerted with dietary phytochemicals and microbial-derived metabolites as potent therapeutic regulators of the tumor microenvironment. Antioxidants 2023, 12, 1056.
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  9. Baker, D.J.; Petersen, R.C. Cellular senescence in brain aging and neurodegenerative diseases: Evidence and perspectives. J. Clin. Investig. 2018, 128, 1208–1216.
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  14. Nakano, N.; Matsuda, S.; Ichimura, M.; Minami, A.; Ogino, M.; Murai, T.; Kitagishi, Y. PI3K/AKT signaling mediated by G,protein-coupled receptors is involved in neurodegenerative Parkinson’s disease. Int. J. Mol. Med. 2017, 39, 253–260.
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  19. Espay, A.J.; Brundin, P.; Lang, A.E. Precision medicine for disease modification in Parkinson disease. Nat. Rev. Neurol. 2017, 13, 119–126.
  20. Zare Harofte, S.; Soltani, M.; Siavashy, S.; Raahemifar, K. Recent advances of utilizing artificial intelligence in lab on a chip for diagnosis and treatment. Small 2022, 18, e2203169.
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Subjects: Biochemistry & Molecular Biology
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Toshiyuki Murai
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