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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.
β-Secretase (BACE1) Inhibitors From Natural Products
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
BACE1 is the transmembrane aspartyl protease that cleaves APP at the β-site. The sequential proteolytic cleavage of APP by BACE1 and γ-secretase leads to the production and release of Aβ peptide in the brain. Therefore, amyloidogenic secretases are key therapeutic targets being currently explored for AD-modifying intervention (Roberds et al., 2001). Several studies report that BACE1 inhibitors hold great potential as a potential strategy to decrease Aβ brain concentrations, thus preventing the progression of AD (Guo, 2006; Salloway, 2008). Since the identification of BACE1, inhibitors covering many different structural classes have been extensively reported in the literature (Vassar, 2004; McArdle and Quinn, 2007; Salloway, 2008). An overview of the recent advances in the identification of BACE1 inhibitor classes obtained from natural products is summarized below.
Pharmacology of Withanolide A
Published in Amritpal Singh Saroya, Contemporary Phytomedicines, 2017
Withanolide A and asiatic acid were investigated for their potential activities against multiple targets associated with Abeta pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Abeta from amyloidbeta precursor protein (AbetaPP), while ADAM10 is involved in non-amyloidogenic processing of AbetaPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Abeta.
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].
High-fat diet exacerbates cognitive and metabolic abnormalities in neuronal BACE1 knock-in mice – partial prevention by Fenretinide
Published in Nutritional Neuroscience, 2022
Kaja Plucińska, Nimesh Mody, Ruta Dekeryte, Kirsty Shearer, George D. Mcilroy, Mirela Delibegovic, Bettina Platt
Because recent evidence suggested that whole-body ablation of Bace1 protects mice from developing DIO [29], we also investigated whether neuronal KI of human BACE1 was sufficient to alter whole-body metabolic homeostasis in mice [30]. Interestingly, neuronal BACE1 KI mice (PLB4) display glucose intolerance, dyslipidemia and a fatty liver phenotype associated with neuronal brain Aβ accumulation, ceramide accumulation, hypothalamic ER stress and altered neuronal insulin signalling [30] as well as increased liver expression and circulating levels of dipeptidyl peptidase 4 (DPP4) [31]. These results suggested that central BACE1 expression drives diabetic-like phenotypes in mice, similar to those observed in mice with intracerebroventricular (icv) infusions of Aβ [32] or ceramides [33], also linked with hypothalamic ER stress. More recently, BACE1-dependent Aβ processing was implicated in the regulation of neuronal leptin resistance in DIO mice [34]. Meakin and colleagues demonstrated that inhibition of hypothalamic Bace1 restored neuronal leptin sensitivity and a healthy metabolic phenotype in DIO mice, via reduced neuroinflammation and improved AgRP/POMC signalling. Emerging evidence also points to a detrimental role of soluble APPβ (sAPPβ), a product of β-site APP proteolysis, in neuronal ER stress and impaired insulin sensitivity [35]. These findings clearly point to a novel, metabolic function of neuronal BACE1.
Stereotaxic-assisted gene therapy in Alzheimer’s and Parkinson’s diseases: therapeutic potentials and clinical frontiers
Published in Expert Review of Neurotherapeutics, 2022
Samar O. El Ganainy, Tony Cijsouw, Mennatallah A. Ali, Susanne Schoch, Amira Sayed Hanafy
In AD, a multitude of preclinical studies implemented RNA-based therapies to slow down or halt disease progression by targeting the BACE1 gene. In one study, Lv et al. [103] co-delivered BACE1-shRNA and epigallocatechin-3-gallate, a strong antioxidant, to the brain of APP/PS1 mice using poly(ethyleneglycol)‐polylactic-co-glycolic acid (PEG-PLGA) polymeric nanoparticles. To enhance brain delivery after intravascular administration, the nanoparticles were conjugated with RVG29 peptide. Treatment of these transgenic mice with the fabricated nanoparticles resulted in down-regulation of the BACE1 gene, decreased Aβ deposition and improved spatial learning as well as memory [103]. In another study, Wang et al. [104] prepared PEG-poly(2-(N,N-dimethylamino) ethyl methacrylate) nanoparticles, functionalized with CGN and Tet1 peptides, to deliver BACE1-targeted siRNA intravascularly in APP/PS1 mice. The treatment decreased the levels of BACE1-mRNA, Aβ deposits and phosphorylated tau in the hippocampus and cerebral cortex, while it enhanced hippocampal neurogenesis [104].