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An Outbreak of Oxidative Stress in Pathogenesis of Alzheimer's Disease
Published in Suvardhan Kanchi, Rajasekhar Chokkareddy, Mashallah Rezakazemi, Smart Nanodevices for Point-of-Care Applications, 2022
Sourbh Suren Garg, Poojith Nuthalapati, Sruchi Devi, Atulika Sharma, Debasis Sahu, Jeena Gupta
OS is considered a chief mediator for the progression of AD. Beta-secretase and gamma-secretase help in the formation of Abeta followed by the cleavage of APP [37]. Beta-secretase and gamma-secretase are two membrane proteases. Beta-secretase is also called the beta-site APP cleaving enzyme (BACE1). Gamma-secretase is a meshwork of multi-proteins that structurally contains presenilin (PS), nicastrin (NCT), and anterior pharynx defective-1 (APH-1). In addition to PS, NCT, and APH-1, gamma-secretase also consists of the presenilin enhancer protein-2 [38] (PEN-2). The 99 amino acids and APP C-terminal fragments are released after the cleavage of APP by BACE-1 at the N-terminal end [39]. Gamma-secretase recognizes this cleavage and signals the transmembrane domain for further cleavage. Thus, the cleavage by gamma-secretase secretes the Abeta peptides [40]. Large numbers of peptides having different lengths are formed via cleavage through these secretases such as Abeta40 and Abeta42 [41]. The 40-amino acid form of peptide is called Abeta40 and the 42-amino acid form of peptide is called Abeta42. Out of these freshly formed peptides, Abeta42 is the more toxic form of the peptide [42]. The rapid self-aggregation of peptides into soluble oligomers contributes to the toxicity of Abeta42. Alpha-secretase is another enzyme that is responsible for the cleavage of APP [43]. The declines in the clearance rate of Abeta peptides lead to their accumulation in the brain which ultimately provokes the pathway of cell-signaling [44]. In addition to cell-signaling, their accumulation also causes the degeneration in synaptic clefts and abnormalities in neurons which cause the neuronal death [45], as the mechanism is depicted in Figure 16.4.
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.