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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
Cholesterol is a sterol having a molecular formula of C17H62O23 and, present in the cell membranes [32]. The abundance of cholesterols in microdomains of cell membranes is called lipid raft [33]. The binding of APP with these rafts commands the β-secretase to insert APP in a monolayer of phospholipids which accumulate the Aβ1–42 peptides through a mechanism called the amyloidogenic pathway [34]. The mechanism of propagation of Aβ is favored by esterified cholesterols. The elimination of excess cholesterols in the brain can be achieved by an oxidation reaction. Oxysterols are liberated as an end product of oxidation. The oxidation of cholesterols is helpful to prevent their accumulation in the brain. Cholesterol is the major component of the brain. The biochemical event of cholesterol 24-hydroxylase lays the formation of 24-hydroxycholesterol, which has the potential to cross the blood-brain barrier [35]. The brain is the major site for their formation. In astrocytes, the liver-X-receptor controlled pathway is responsible for mediating the efflux of apoE cholesterols. Together, oxysterol and efflux of apoE upregulate the cholesterol homeostasis in the brain which directly links with the progression of AD [36].
Inside Alzheimer's Disease Diagnosis
Published in Parimelazhagan Thangaraj, Lucindo José Quintans Júnior, Nagamony Ponpandian, Nanophytomedicine, 2023
Gomathi Rajkumar, Murugan Rajan, Mairim Russo Serafini, Narendra Narain, Adriano A.S. Araujo, Lucindo José Quintans Júnior, Lijing Ke
The amyloid precursor protein (APP), is a central protein that plays a key role in the loss of neurons (cholinergic) in the hippocampus and cortex of the brain. Amyloid β (Aβ) is the product of proteolytic cleavage of APP. Under normal condition, α-secretases and γ-secretases cleave to APP-forming nonaggregating fragments. However, a dysfunction is observed when APP is cleaved by β-secretases and γ-secretases, resulting in aggregation of Aβ fragments in the intraneuronal network forming amyloid plaques. The oligomerization of Aβ plaques are found to cause neuronal cell death via intracellular neurofibrillary tangle (NFTs) formation and synaptic dysfunction, resulting in neurotoxicity in AD (Takahashi et al., 2017).
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 role of herbal alternatives in circumventing Alzheimer’s disease through multi-targeting approach - a review
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Sunil K Ravi, Balenahalli Narasingappa Ramesh, Shilpa Kj, Jagadesha Poyya, Jyothsna Karanth, N.G Raju, Chandrashekhar G Joshi
α-secretase enzyme proteolytically cleaves the APP via the non-amyloidogenic pathway at L688 residue located within the Aβ sequence and thereby preventing the formation of Aβ (Figure 2). The first enzyme for α-secretase was proposed in 1998, when ADAM17, also known as tumor necrosis factor-converting enzyme (TACE), was reported to possess α-secretase activity [118]. Later, ADAM9 and ADAM10 were also shown to have α secretase activity [119]. These three proteins belong to the ADAM (a disintegrin and metalloprotease) family. It is reported that mutations in ADAM10 alter the processing of APP and lead to AD by increasing Aβ levels [120]. Thus, a promising yet underestimated approach to overcome AD would be, activating α-secretase processing of βAPP.