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      Advances with RNA interference in Alzheimer’s disease research

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          Abstract

          Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized clinically by memory and cognitive dysfunction. Unfortunately, there is no effective therapeutic method for AD treatment or ways to halt disease progression. Many mechanisms are involved in the disease, including genes mutation and protein dysfunction. RNA interference (RNAi) technology may potentially be able to control AD. It can inhibit the protein expression of specific genes by activating a sequence-specific RNA degradation process. This is a powerful tool with which to study gene function, investigate the mechanism of the disease, and validate drug targets. In this review, we highlight the advances in RNAi technology in the investigation and treatment of AD.

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          Most cited references 72

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          Alzheimer's disease.

          Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.
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            Knocking down barriers: advances in siRNA delivery

            Key Points RNA interference (RNAi) is a fundamental pathway in eukaryotic cells by which sequence-specific small interfering RNA (siRNA) is able to silence genes through the destruction of complementary mRNA. RNAi is an important therapeutic tool that can be used to silence aberrant endogenous genes or to knockdown genes essential to the proliferation of infectious organisms. Delivery remains the central challenge to the therapeutic application of RNAi technology. Before siRNA can take effect in the cytoplasm of a target cell, it must be transported through the body to the target site without undergoing clearance or degradation. Currently, the most effective synthetic, non-viral delivery agents of siRNA are lipids, lipid-like materials and polymers. Various cationic agents including stable nucleic acid–lipid particles, lipidoids, cyclodextrin polymers and polyethyleneimine polymers have been used to achieve the successful systemic delivery of siRNA in mammals without inducing significant toxicity. Direct conjugation of delivery agents to siRNA can facilitate delivery. For example, cholesterol-modified siRNA enables targeting to the liver. RNAi therapeutics have progressed to the clinic, where studies are being conducted to determine siRNA efficacy in treating several diseases, including age-related macular degeneration and respiratory syncytial virus. Moving forward, it will be important to pay close attention to the potential nonspecific immunostimulatory effects of siRNA. Modifications to siRNA can be used to minimize stimulation of the immune system, and an increased emphasis must be placed on performing proper controls to ensure that therapeutic effects are sequence-specific.
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              Alzheimer's disease: strategies for disease modification.

               Martin Citron (2010)
              Alzheimer's disease is the largest unmet medical need in neurology. Current drugs improve symptoms, but do not have profound disease-modifying effects. However, in recent years, several approaches aimed at inhibiting disease progression have advanced to clinical trials. Among these, strategies targeting the production and clearance of the amyloid-beta peptide - a cardinal feature of Alzheimer's disease that is thought to be important in disease pathogenesis - are the most advanced. Approaches aimed at modulating the abnormal aggregation of tau filaments (another key feature of the disease), and those targeting metabolic dysfunction, are also being evaluated in the clinic. This article discusses recent progress with each of these strategies, with a focus on anti-amyloid strategies, highlighting the lessons learned and the challenges that remain.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2013
                22 February 2013
                : 7
                : 117-125
                Affiliations
                [1 ]Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine
                [2 ]School of Pharmacy, Shanghai Jiaotong University, Shanghai
                [3 ]Department of Neurology, Jinshan Hospital, Fudan University, Shanghai, People’s Republic of ChinaSchool of Pharmacy, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240, People’s Republic of China Tel/fax +86 21 3420 5072 Email yuanweien@ 123456126.com
                Author notes
                Correspondence: Zhenguo Liu Department of Neurology, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of China Tel/fax +86 21 6579 0000 Email zhenguoliu2011@ 123456yahoo.com.cn
                [*]

                These authors contributed equally to this work

                Article
                dddt-7-117
                10.2147/DDDT.S40229
                3582316
                23459401
                © 2013 Chen et al, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Review

                Pharmacology & Pharmaceutical medicine

                rnai, â-amyloid, tau, amyloid precursor protein

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