مقالات پذیرفته شده در هفتمین کنگره بین المللی زیست پزشکی
Role of miRNAs in Alzheimer’s Disease
Role of miRNAs in Alzheimer’s Disease
Negin Hashmi1*,1,*
1. Msc of Molecular Genetic Department of Genetics, Tehran Branch, Islamic Azad University, Iran.
Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disease and it is the most common cause of dementia worldwide. It is characterized by neuronal death, loss of synaptic function, and atrophy in different brain areas, with consequent loss of cognitive functions and memory. AD is characterized by neuritic (or amyloid) plaques and neurofibrillary tangles (NFTs). Neuritic plaques are extracellular accumulations of beta-amyloid (Aβ). Many studies have suggested that Aβ regulates neuronal and synaptic activities. Its accumulation in the brain plays a crucial role in initiating the disease and triggering a complex pathological cascade, which leads to neuronal damage. Aβ peptide derives from the enzymatic proteolysis of the amyloid precursor protein (APP), a protein that physiologically plays an important role in brain homeostasis. The first pathway involved in APP processing is the non-amyloidogenic α-secretase-mediated pathway. APP cleavage by α-secretase generates sAPPα, a soluble molecule that has a probable neuroprotective function. Indeed, this peptide plays an important role in the plasticity and survival of neurons and in the protection against cytotoxicity. MiRNAs (or microRNAs) are small noncoding RNAs that play a significant role in the post-transcriptional regulation of gene expression in eukaryotes. The miRNAs exert their action in post-transcriptional gene silencing, binding to the coding region as well as the 3′ and 5′ untranslated region (UTR) of the messenger RNAs (mRNAs). The aim of this study was to investigate Role of miRNAs in Alzheimer’s Disease.
Methods: This review study has been written from scientific databases such as Science Direct, Springer, Google Scholar, and PubMed.
Results: The results of a number of studies are as follows:
Higaki et al. conducted a study in order to correlate the differential expression of the miRNA-200 family (miRNA-200a, -141, -429, -200b, -200c) in the initial phases of AD in the mouse brain Tg2576. Tg2576 mice overexpress the APP protein (Swedish KM670/671NL mutation). Analysis of the total RNA microarray extracted from cortical tissues of mice revealed that miRNA-200a, -141, -429, -200b, and -200c were upregulated only in Tg2576 mice of 10 months of age. These results suggest that some miRNAs may respond to the early Aβ accumulation. In addition, an in vitro study was conducted on primary murine neuronal cells (PMNC) isolated from the cortical tissues of mice in order to verify if the expression of miRNA-200b and miRNA-200c are altered in response to neuronal damage induced by Aβ1. The treatment with Aβ of the PMNC cells induced the upregulation of miRNA-200b or -200c. Subsequently, the cells were transfected with miRNA-200b/c demonstrating that the upregulation of miRNA-200b and miRNA-200c reduced the secretion of Aβ in the conditioned medium. In order to evaluate the effect of miRNA-200b/c in vivo, Tg2576 mice were treated with miRNA-200b/c by intracerebroventricular injection. This experiment confirmed what was obtained in vitro, suggesting that miRNA-200b and miRNA-200c may be potential therapeutic targets in AD. Liu et al. conducted a study to evaluate the expression of miRNA-220b, miRNA-135a, and miRNA-429 in the hippocampus of APP/PSEN1 transgenic mice. Microarray miRNA analysis showed that these miRNAs were significantly upregulated. In addition, this analysis was supported by bioinformatics tools that disclose the potential interaction between APP and BACE-1, an enzyme responsible for the production of Aβ.
Conclusion: level of Aβ and other proteins. MiRNAs may be a therapeutic target with great research potential in the current or a long period in the field of AD. In contrast to conventional drugs, miRNAs are highly targeted. MiRNAs can directly bind to the corresponding signalling pathways to regulate the expression of the target protein. However, miRNAs need to be administered systemically to the central nervous system to function in a large dose. It is difficult for them to pass through the blood-brain barrier, and their relative utilization is extremely low. Local brain drug delivery has significant effects in animal treatment research, while local brain drug delivery is difficult to achieve in current clinical treatments. In the future, when clinical drug delivery technology is further improved, local drug delivery is expected to be used to deliver miRNAs to the brain to treat AD.