The Contribution and Therapeutic Potential of Epigenetic Modifications in Alzheimer’s Disease

Wood, Ian C.

doi:10.3389/fnins.2018.00649

Cited by 32 publications

(18 citation statements)

References 96 publications

(121 reference statements)

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“…Activation of NOX in acute injury and inflammation is clear, however, neurodegeneration is a chronic disease characterised by progressive neuronal loss and more subtle changes to the brain parenchyma that have been described as “the manifestation of a faster ageing process” [ 105 ]. Therefore, it is important to describe microglial NOX in this accentuated ageing as well as in response to more acute stimuli.…”

Section: Microglial Nox Is Activated In Inflammation and Neurodegementioning

confidence: 99%

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

2020

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Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined; thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2) and activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation; thus intracellular ROS signalling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 (NQO1), is promoted by transcription factor Nrf2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia (LDAM) may also represent a double-edged sword in neurodegenerative disease by sequestering peroxidised lipids in non-pathological ageing but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics.

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Section: Microglial Nox Is Activated In Inflammation and Neurodegementioning

confidence: 99%

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

2020

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“…Methylation can serve as a repressor or activator of gene expression depending on the site of histone lysine modification [ 131 ]. Administration of specific DNMT inhibitors can help alleviate pathological conditions that arise from hypermethylation.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease

Balmik

Chinnathambi

2021

Cell Commun Signal

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Neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s disease involves abnormal aggregation and accumulation of toxic proteins aggregates. Post-translational modifications (PTMs) of the causative proteins play an important role in the etiology of disease as they could either slow down or accelerate the disease progression. Alzheimer disease is associated with the aggregation and accumulation of two major protein aggregates—intracellular neurofibrillary tangles made up of microtubule-associated protein Tau and extracellular Amyloid-β plaques. Post-translational modifications are important for the regulation of Tau`s function but an imbalance in PTMs may lead to abnormal Tau function and aggregation. Tau methylation is one of the important PTM of Tau in its physiological state. However, the methylation signature on Tau lysine changes once it acquires pathological aggregated form. Tau methylation can compete with other PTMs such as acetylation and ubiquitination. The state of PTM at these sites determines the fate of Tau protein in terms of its function and stability. The global methylation in neurons, microglia and astrocytes are involved in multiple cellular functions involving their role in epigenetic regulation of gene expression via DNA methylation. Here, we have discussed the effect of methylation on Tau function in a site-specific manner and their cross-talk with other lysine modifications. We have also elaborated the role of methylation in epigenetic aspects and neurodegenerative conditions associated with the imbalance in methylation metabolism affecting global methylation state of cells.

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“…Of those over 65, 10.3% had Alzheimer's disease. 18.7 percent of people aged 75-84 and 2.47 percent of those over 85 years old (44). Age is the largest risk factor for Alzheimer's disease and the prevalence of this disease increases with age.…”

Section: Figure 1: the Frequency Of Some Risk Factors And Complicatiomentioning

confidence: 99%

The communication Between Diabetes and Alzheimer's Disease: a study on diabetic patients referring to health centers in three cities of Khuzestan province

Madmoli

Khodadadi

et al. 2019

Int Res in Med and Heal Sci

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Introduction: Epidemiological studies suggest convincing evidence for a meaningful relationship between type 2 diabetes and dementia. It also shows that type 2 diabetes is a major cause of Alzheimer's disease. Given the Iranian population's profile of about 31 million middle-aged people, in the next two decades, older people will form a large population. On the other hand, the increase in Alzheimer's in the elderly is due to the prevalence of this disorder and the adverse effects and adverse effects in the next two decades. And so far, quantitative research has been conducted to investigate the risk of Alzheimer's disease in diabetic patients in Khuzestan province. Therefore, this study titled "The communication Between Diabetes and Alzheimer's Disease: study on diabetic patients referring to health centers in three cities of Khuzestan province" was done. Materials and Methods: This retrospective cross-sectional descriptive study was conducted on diabetic patients hospitalized in Shoushtar, Behbahan, and Abadan, between 2015 to 2017. The files of these patients who were diagnosed with diabetes and referred to medical centers in the mentioned cities that were extracted from medical records of city hospitals and entered the study. Data were then entered into SPSS software version 20. Data were analyzed using descriptive statistics, analytical tests and the significance level of P <0.05. Results: In this study, the mean age of patients was 57.00 ± 46.23 years. A statistically significant relationship was found between diabetes and those with Alzheimer's disease (p = 0.006). However, there was no significant relationship between diabetes and those with a history of cardiovascular disease (p = 0.09). There was no significant relationship between education and those with Alzheimer's disease (0.06). But a statistically significant relationship was found between jobs with those with Alzheimer's disease (0.003). Conclusion: In this study, there was a significant relationship between diabetes and those with Alzheimer's disease. Therefore, this study showed the risk of Alzheimer's disease in diabetic patients in the three mentioned cities. More epidemiological and clinical research is needed to investigate the relationship between these two diseases in a wider and larger volume.

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The Contribution and Therapeutic Potential of Epigenetic Modifications in Alzheimer’s Disease

Cited by 32 publications

References 96 publications

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease

The communication Between Diabetes and Alzheimer's Disease: a study on diabetic patients referring to health centers in three cities of Khuzestan province

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