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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.
The Neurodegenerative Characteristics of Alzheimer’s Disease and Related Multi-Target Drug Design Studies
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Hayrettin Ozan Gülcan, Ilkay Erdogan Orhan
BACE-1 enzyme is a member of aspartic protease enzymes. It cleaves APP both at the N-terminus and between E10 and V11 (Hills et al., 2007). There is another BACE enzyme (i.e., BACE-2) that also cleaves APP from different sides. What makes BACE-1, but not BACE-2, as a target is that BACE-1 inhibition absolutely abolishes Aβ production, while BACE-2 inhibition does not display a difference (Fluhrer et al., 2002). Following the initial identification of BACE-1 as a critical enzyme in amyloidogenic pathway, many compounds have been designed and tested for their BACE-1 inhibitory potential. Some of them even have been employed in clinical trials. Although majority of the compounds were found very successful both in human and animal experiments, none of them has been reached to the market yet (Hills et al., 2007). The basic reason is their deficiency in cognitive enhancement (Vassar, 2014). Some of these BACE-1 inhibitors used in clinical trials are shown in Table 12.1.
FRET Reporter Molecules for Identification of Enzyme Functions
Published in Grunwald Peter, Biocatalysis and Nanotechnology, 2017
Jing Mu, Hao Lun Cheong, Bengang Xing
β-Secretase (BACE) is a membrane bound aspartic protease ubiquitously expressed in the brain and pancreas tissues. BACE was identified as the proteolytic enzyme that cleaves amyloid precursor protein (APP). Proteolytic cleavages of APP by BACE, creates a C99 membrane-bound C-terminal fragments, which are further processed by secretase to release toxic amyloid-β peptides. Such insoluble peptides aggregate to induce neurodegeneration, which are known as Alzheimer’s disease (AD). Therefore, effective tools to elucidate the secretase functions, especially in cellular levels and living animal are quite necessary for better understanding the pathological feature of AD (Hardy et al., 2002; Evin et al., 2010).
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].