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Lipid Nanocarriers for Oligonucleotide Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Andreia F. Jorge, Santiago Grijalvo, Alberto Pais, Ramón Eritja
The concept of using exosomes as carriers of siRNA into the brain was previously reported by Alvarez-Erviti et al. [141]. In this work, the authors injected intravenously purified RVG peptide-targeted exosomes loaded with exogenous glyceraldehyde 3-phosphate dehydrogenase (GAPDH) siRNA through electroporation in mice. Results have shown a potent silencing activity, up to 60% of mRNA and 62% of protein knockdown of BACE1, a therapeutic target in Alzheimer’s disease. Since this seminal work, other studies have been carried out on the role of exosomes in brain tumour and neurological disorders [142]. One of the most explored strategies to achieve BBB crossing is to engineer targeting ligands into exosomal membrane. The encapsulation of a hydrophobic modified siRNA was also recently tested, showing a statistically significant knockdown of HTT mRNA of ~35% [143]. Despite these encouraging results many hurdles must still be overcome to achieve a wider clinical application such as optimisation of the methods of purification and gene loading, selection of exosomes donor cells, minimisation of toxicity and enhancement of their pharmacokinetic properties.
Aptamers as Therapeutic Tools in Neurological Diseases
Published in Rakesh N. Veedu, Aptamers, 2017
Lukas Aaldering, Shilpa Krishnan, Sue Fletcher, Stephen D. Wilton, Rakesh N. Veedu
AD is characterized by two major abnormalities, abnormal extracellular amyloid-β protein disposition and intracellular neurofibrillary tangle (NFT) formation, leading to neuronal degeneration [48]. The amyloid-β protein is generated by the sequential cleavage of the amyloid-β precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1) [49]. This enzyme contains a short cytoplasmic tail (B1-CT). Rentmeister et al. identified an RNA aptamer that binds specifically to the B1-CT tail without interfering with the B1-CTregulated BACE1 transport [50]. It is remarkable that this aptamer is able to discriminate binding regions within a 3 kDa peptide. Therefore, this aptamer could be used to further investigate and elucidate B1-CT function without affecting cellular localization or other important biological activities.
Nanotechnology in Medicine: Drug Delivery Systems
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Drug Delivery Approaches and Nanosystems, 2017
Elena Campano-Cuevas, Ana Mora-Boza, Gabriel Castillo-Dalí, AgustíN. RodríGuez-Gonzalez-Elipe, MaríA-Angeles Serrera-Figallo, Barranco Angel, Daniel Torres-Lagares
Regarding to the inhibition of Aβ, the main proposed target has been the β secretase, referred to as β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), which initiates the Aβ production. BACE1 is a key therapeutic target for Alzheimer treatment and several BACE1 inhibitors have entered in clinical trials (Yan et al., 2014). The inhibition can be carried out by gene suppression or with targeted nanocarriers, as for example antibodies used as therapeutic agents. In addition, another proposal is that antibodies recruit Aβ in the circulation (Banks, 2012; DeMattos et al., 2002), preventing its accumulation in the blood and crossing to the CNS.
Neuroprotective effect of quercetin through targeting key genes involved in aluminum chloride induced Alzheimer’s disease in rats
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Hala A Elreedy, Asmaa M. Elfiky, Asmaa Ahmed Mahmoud, Khadiga S. Ibrahim, Mohamed A Ghazy
β-amyloid converting enzyme 1 (BACE1) is the major β-secretase [37,38]. Also, BACE1 is a first protein that cleavages APP forming Aβ in an amyloid pathway. Several studies have demonstrated that BACE1 could be a potential curative target. Mice that are BACE-1 knockout do not have severe phenotypic defects and do not develop measurable quantities of Aβ [39,40]. Our results showed that the level of BACE1 gene expression was significantly elevated in the hippocampal tissues of the AlCl3 group when compared to the normal control. On the other hand, a decrease in BACE1 gene expression was observed in the co-administration of AlCl3 with Q at 50 mg kg-1 to the AlCl3 -induced AD rat. The last findings are consistent with in vitro study by Shimmyo and Kihara [41] who exhibited that quercetin decreases BACE1 activity in a cell-free system with an IC50 of 5.4 ± 0.5 µM, whereas, in a neural cell system, quercetin as well shown BACE1 decreasing activity with IC50 of 50 µM. Moreover, another study evaluated how quercetin affected old mice’s neurotoxicity caused by excessive cholesterol. They found that mice treated with quercetin showed a decrease in BACE1 expression [42].