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Role of Oxidative Stress in the Onset of Alzheimer’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Tasnuva Sarowar, Md. Hafiz Uddin
The abeta generated by the amyloidogenic pathway is 40 amino acids long (abeta40). Several missense mutations have been identified in the coding region of APP, which alter the length and properties of abeta. Probably the most discussed of these mutations is the Swedish mutation (K670N, M671L), which alters the cutting site of beta secretase, thus yielding abeta with 42 amino acids (Mullan et al. 1992). This abeta42 has different physico-chemical properties than abeta40 (Yankner and Lu 2009). The abeta42 peptides rapidly form a beta-sheet structure, which is harder to degrade than the normal random coiled abeta40 (Barrow and Zagorski 1991). Abeta plaque formation follows a structural hierarchy, starting from monomer, dimer, trimer to small oligomer, protofibrills, fibrils, and plaques (Finder and Glockshuber 2007). Lesser numbers of abeta42 monomer are required to form such fibrils compared to abeta40. Thus, individuals harboring the Swedish mutation develop early-onset AD.
Cognitive Functions, Attention-Deficit Hyperactivity Disorders, and Alzheimer’s Disease
Published in Divya Vohora, The Third Histamine Receptor, 2008
Maria Beatrice Passani, Patrizio Blandina, Kaitlin E. Browman, Gerard B. Fox
AD-relevant transgenic models can be broadly classified into mice that model the amyloid beta pathology or mice that model the tangle (tau) pathology, although some lines have been designed in an attempt to model both. Of the mice modeling, the amyloid beta pathology, perhaps one of the best known, is the commercially available Tg2576 mouse [123], which overexpresses the human APP Swedish mutation. This line exhibits amyloid plaques from 9 to 12 months of age onward in key brain regions such as the hippocampus, entorhinal, and frontal cortex as well as increased levels of soluble amyloid beta oligomers and vascular amyloid. No neurodegeneration is evident; however, and in our hands, these mice have proven very difficult to work with in behavioral studies of cognitive function. Thus, although useful, the Tg2576 line is an incomplete model of AD. Other popular mice modeling amyloid beta pathology include APP/Lo London mutation, APP23 Swedish mutation, and the PDAPP Indiana mutation (see Ref. 121 for a review). Intriguingly, a relatively recent transgenic line, the so-called triple transgenic model of AD (3 × Tg-AD), exhibits plaques and tangles as well as intracellular amyloid beta and synaptic dysfunction [124]. This line incorporates the Tg2576 Swedish mutation as well as human tau and presenillin (PS1) mutations. Reversible behavioral deficits are reported for 3 × Tg-AD mice as well as many of the others mentioned earlier, but it is difficult to rigorously and independently validate these data. Transgenic lines modeling tau pathology (e.g., JNPL3) or amyloid and tau pathology (e.g., TAPP) exhibit tangles in spinal cord and brain-stem and suffer from marked motor disturbances and are not generally suitable for cognitive testing. An exception to this is the 3 × Tg-AD mouse line, exhibiting cognitive impairment that correlates with intraneuronal amyloid beta, which precedes extracellular Aβ deposition as plaques and the subsequent increase in tau pathology [94]. Similarly, the APP/tau line develops amyloid deposits, neurofibrillary tangles, neuronal loss, as well as cognitive impairment.
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
APP is a transmembrane glycoprotein that has a receptor-like structure which is crucial for neurite elongation, branching and sprouting [31]. APP can pass through two different proteolytic pathways: the non-amyloidosis pathway, which inhibits Aβ formation and appears to be a protective pathway, along with the amyloidosis pathway, which results in Aβ generation [32]. Aβ is produced through successive cleavage of APP by beta- and gamma-secretases. As a consequence, Aβ contents correlate with the expression of APP, beta and gamma-secretases [33,34]. In our study, the AlCl3-induced AD rats revealed significantly up-regulation of APP compared with normal group, which is the most important hallmark of AD [35]. However, there is a significant down-regulation in expression level of APP in the co-administration of AlCl3 with Q 50 mg kg-1 to the AlCl3-induced AD rats. These results are in line with [13], and they found that the expression level of APP decreased in the AlCl3 + QT-SPIONs group. Also, an in vitro study [36] demonstrated that rutin and quercetin prevented the development of Aβ fibrils and disaggregated Aβ fibrils APP in Swedish mutation (APPswe) cells.
Lactobacillus Spp.-Enhanced Memory is Strain-Dependent and Associated, in Part, with Amyloidogenic and anti-Oxidant/Oxidative Stress Interplay in Amyloid Beta Precursor Protein Transgenic Mice
Published in Journal of Dietary Supplements, 2023
Nor Amalina Ahmad Alwi, Siong Meng Lim, Vasudevan Mani, Kalavathy Ramasamy
The present animal study was approved by the Committee on Animal Research and Ethics (CARE) of the UiTM (Reference Number: 20/2013). The animals were handled and managed in accordance to the Guide for the Care and Use of Laboratory Animal (20). Both the Department of Biosafety and Institutional Biosafety Committees were also being officially notified of the contained use of these living modified organisms [Reference Number: JBK(S) 602-1/3 Jld.10(31)]. The animals used in the present study were male R1.40 transgenic mice (n = 18) and C57BL/6J wild type mice (n = 6) of about 10-12 months old and weighed 35-40 g. The mice were purchased from the Jackson Laboratory, Maine, USA. The R1.40 rodents carried the familial Alzheimer’s disease (FAD) Swedish mutation K670N/M671L and expressed all mRNA and protein isoforms of the human APP. The present study had selected 10 months old APP transgenic mice given that they usually yield a significant increase in APP and Aβ production as early as 3 months old with Aβ plaque deposition starts to take place as early as 13.5 months old (21,22). Prior to deposition of senile plaques, APP transgenic mice would be presented with neuronal cell cycle events which were dependent upon amyloidogenic processing of APP, coinciding with elevated neuroinflammation (23–25). The C57BL/6J was included as wild type control, representing the “genetic background” of R1.40 transgenic mice. The animals were housed in standard laboratory conditions with a natural light-dark cycle (12 h each) and access to food and water ad libitum. Experiments were carried out between 0900 and 1800 h.
Multitarget drugs as potential therapeutic agents for alzheimer’s disease. A new family of 5-substituted indazole derivatives as cholinergic and BACE1 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Pedro González-Naranjo, Concepción Pérez, Marina González-Sánchez, Adrián Gironda-Martínez, Eugenia Ulzurrun, Fernando Bartolomé, Marcos Rubio-Fernández, Angeles Martin-Requero, Nuria E. Campillo, Juan A. Páez
Briefly, BACE1 in vitro assays were carried out using fluorescence resonance energy transfer (FRET). An APP-based peptide substrate (rhodamine-EVNLDAEFK-quencher, Km of 20 μM) carrying the Swedish mutation and containing rhodamine as a fluorescence donor and a quencher acceptor at each end was used. The intact substrate is weakly fluorescent and becomes highly fluorescent upon enzymatic cleavage. The assays were conducted in 50 mM sodium acetate buffer, pH 4.5, at a final enzyme concentration of 1 U/mL. Inhibitor screening was performed at 10 μM. The mixture was incubated for 60 min at 25 °C under dark conditions and then stopped with 2.5 M sodium acetate. Fluorescence was measured with a FLUOstar Optima (BMG Labtechnologies GmbH, Offenburg, Germany) microplate reader at 545 nm excitation and 585 nm emission. The assay kit was validated by the manufacturer.