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Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Familiar earlγ-onset AD is coined by mutations in the APP (amyloid precursor protein gene, the presenilin1 (PSEN1), and the presenilin2 (PSEN2) gene (for a discussion of the pathological and physiological functions of presenilins, see Vetrivel et al., 2006); first- and second-generation transgenic (Tg) mouse models (the latter lack additional phenotypes related to overexpression) have been developed that overexpress APP or presenilin, or both, and used for familiar Alzheimer’s disease preclinical studies. Sasaguri et al. (2017) reviewed APP mouse models and respective studies performed with second-generation mice. On the other hand, sAD depends on a variety of genetic and environmental factors including epigenetic mechanisms, and its origin is only poorly understood to date.
Vitro Alzheimer’s Disease Modeling Using Stem Cells
Published in Hyun Jung Kim, Biomimetic Microengineering, 2020
Hyun-Ji Park, Song Ih Ahn, Jeong-Kee Yoon, Hyunjung Lee, YongTae Kim
Aβ is a small polypeptide that consists of about 40 amino acid residues, a fragment of a large amyloid precursor protein (APP; Figure 11.1; Kametani and Hasegawa 2018). The APP is a transmembrane protein associated with neuronal outgrowth, axonal transport, and neuronal development (Kang et al. 1987). In the normal physiological status, APP is degraded into Aβ fragments by β-secretase 1 (BACE 1) and γ-secretase (a complex containing presenilin 1), a process known as regulated intercellular proteolysis. Then Aβ fragments are secreted outside the cell and degraded rapidly (Kametani and Hasegawa 2018). In detail, the extracellular domain of APP is cleaved by α-secretase (TACE/ADAM) and BACE 1 (Vassar et al. 1999, Lammich et al. 1999), which produce N-terminal fragments of soluble APP, named sAPPα and sAPPβ, respectively. Following the cleavage, the membrane-bound C-terminal residues, C83 and C99, are further cleaved at three different sites (γ, ε, and ζ) by γ-secretase complex, including Aph-1, Pen 2, presenilin-1, and nicastrin, with the incision at the γ-site, finally releasing Aβ peptides from the membrane (Francis et al. 2002, De Strooper et al. 1998, Takasugi et al. 2003, Yu et al. 2000). The γ-secretase complex is responsible for the production of released Aβ peptides with the different numbers of amino acid residues. Specifically, the mutations of presenilin 1/2 affect the formation and processing of Aβ residues (Xu et al. 2016). In normal condition, Aβ 40 is the main product that is released outside the cell and consequently digested. However, with aging or under pathological conditions, the abnormal incision of 42 amino acid residues increases the production of Aβ 42 instead of Aβ 40. The genetic mutations of APP, which are discovered in the early-onset familial AD, are clustered near β- or γ-secretase cleavage sites and associated with an increase in the production of Aβ 42 (Kang et al. 1987). Other familial AD (fAD) mutations have been found in presenilin 1/2, a component of γ-secretase complex (Svedruzic, Popovic, and Sendula-Jengic 2015). The mutation of presenilin 1/2 leads to an increase of APP C-terminal fragments, mostly Aβ 42. Since Aβ 42 is more hydrophobic than Aβ 40, it has the prominent ability to oligomerize and accumulate to form the toxic amyloid fibrils.
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
Gamma-secretase is an intramembrane aspartyl protease which engaged in Alzheimer’s disease through the proteolysis of APP. Thus, gamma-secretase creates the pathogenic Aβ 1–42 peptide that causes amyloid plaques [43,44]. A protein called Presenilin I (PSEN1) belongs to the aspartic protease family and is involved in the control of intramembrane proteolysis [8]. PSEN1 was believed to be a central, catalytic moiety of the gamma-secretase complex. PSEN1 was reported to be capable of cleaving substrates in the absence of Nicastrin (NCT), APH1 and presenilin enhancer-2 (PEN-2) in an activity assay performed in the liposomes [45]. Therefore, PSEN1 is a candidate target gene in drug design against AD. In the current research, we evaluated the levels of PSEN1 and APH1, two different components of gamma-secretase, in the hippocampus of rat brains. Both PSEN1 and APH1 levels were elevated in the AlCl3-induced AD group in comparison with the normal group. Meanwhile, PSEN1 gene expression level was significantly decreased in co-administration of AlCl3 with Q 50 mg kg-1 to AlCl3-induced AD rat. Suggesting that polyphenols could act as an inhibitor of PSEN1, a study by Lakey-Beitia and Berrocal [46] intended that polyphenols could occupy the active site of gamma-secretase (displacing the water molecule needed for catalysis by the enzyme), would inactivate the enzyme and decrease Aβ formation. On the other hand, Q at 50 mg kg-1 to AlCl3 -induced AD rats showed no significant effect on APH1gene expression compared to AlCl3 group.