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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 structure of the three secretase enzymes are important. The alpha secretase comprises metalloproteases of TNFalpha and disintegrin matrix (Periz and Fortini 2000). The beta secretase or BACE (beta site APP cleaving enzyme) has different isoforms which give rise to different populations of abeta (Vassar and Citron 2000). The gamma secretase is a multiprotein complex with presenilin 1 (PSEN1), nicastrin, Aph-1, and presenilin 2 (PSEN2) (Steiner 2004). Similar to BACE, different PSEN1 and PSEN2 isoforms process APP in different manner. To generate abeta, the APP has to be cleaved by gamma and beta secretase, and various signaling pathways are associated with this. It has been shown that oxidative stress enhances beta and gamma secretase activity and increases abeta production (Tamagno et al. 2002, Oda, Tamaoka, and Araki 2010).
Cognitive Improvement, Neuroprotective, and Nootropic Effect of Medhya Rasa¯yana Drugs in Alzheimer’s Disease
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
Rinki Kumari, Jasmit Singh, Bhargawi Mishra, Anamika Tiwari, Abaidya Nath Singh
Another gene, the amyloid precursor protein gene (APP), is present on chromosome 21q and synthesizes the protein, APP. APP is present in the plasma membrane as a transmembrane protein, and has both intracellular and extracellular parts. Normally, cleavage by α-secretase is followed by cleavage by γ-secretase, which results in the formation of soluble proteins. Alpha- and β-secretase cleavage sites are present on the surface of the cell, whereas γ-secretase has a cleavage site in the intra-membrane region of the protein. In an AD patient, β-secretase carries out the first cleavage, which is followed by cleavage by γ-secretase, resulting in the generation of the Aβ protein, which becomes aggregated and is deposited in various parts of the brain to cause neuronal degeneration (Priller et al., 2006). Aβ protein is also deposited in the walls of the blood vessels, where it weakens them, resulting in amyloid angiopathy.
Targeting Notch Pathways
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jennifer O’Neil, A. Thomas Look
The multicomponent γ-secretase enzyme complex that cleaves Notch to release the NICD also cleaves the amyloid precursor protein, leading to the production of plaques in Alzheimer’s patients. As a result, γ-secretase inhibitors have already been developed for use as drugs. Treatment of T-ALL cell lines with γ-secretase inhibitors leads to G0/G1 arrest, demonstrating that the cells are dependent on Notch signaling for their growth, and suggesting that activation of the Notch pathway contributes to T-cell transformation by influencing cell cycle progression (19). Subsequent studies have shown that MYC is a key target of Notch in T-ALL (27,32,33).
Role of aluminum exposure on Alzheimer’s disease and related glycogen synthase kinase pathway
Published in Drug and Chemical Toxicology, 2023
Sonia Sanajou, Pınar Erkekoğlu, Gönül Şahin, Terken Baydar
The deposition of Aβ plaques is believed to cause loss of basal forebrain cholinergic neurons, damage to axons dendrites, and loss of synapses, which in turn cause cognitive impairment. However, the exact mechanism behind most AD cases is still unknown. Aβ is a normal APP cleavage in the human central nervous system (CNS). Aβ, with a half-life of approximately 9 h, usually turns over rapidly in the human CNS. However, Aβ turnover kinetics is altered in AD (Skalny et al.2021). The plaque can be neurotic, dense-cored or compact. Proteolytic cleavage enzymes, β-secretase, and γ-secretase cleave APP into fragments with a certain number of amino acids. The formation of Aβ40 and Aβ42 fragments has mainly reported AD. The insoluble forms of Aβ monomers are from the amyloid fibrils, and the soluble form is distributed in the brain. As humans age, the rate of Aβ turnover and clearance decreases. The chance of Aβ aggregation and conformation change increases though the exact mechanism behind this phenomenon is still under investigation (Lauretti et al.2022).
Natural inhibitors for acetylcholinesterase and autophagy modulators as effective antagonists for tau and β-amyloid in Alzheimer’s rat model
Published in Biomarkers, 2023
Mervat Hassan, Hisham Ismail, Olfat Hammam, Abdullrahman Elsayed, Othman Othman, Sohair Aly Hassan
Physiologically, tau is a microtubule-associated protein that modulates microtubule stability and axonal transport (Kadavath et al. 2015). Tau is a natively unfolded protein with a low aggregation tendency and is extremely soluble. Nevertheless, tau aggregation is a hallmark of a plethora of neurodegenerative disorders, including Alzheimer’s disease (Hassan and Kadry 2021). Accordingly, in the current study tau, β-amyloid, (AchE) levels were significantly elevated, while (Ach) was markedly reduced in the intoxicated model compared to the normal at (P < 0.0001). It was not surprising that the intoxicated group had been exposed to strong oxidative stress agents (150 & 300 mg/kg AlCl3 and D-gal respectively), which participate in a series of activation mechanisms. First, activation of phosphorylated enzymes which increased the tendency of tau for more aggregation. Second, activation of beta-secretase which increased the breakdown of amyloid precursor protein (APP) and encouraged more deposition of amyloid-beta (Aβ) plaque on the brain cells. Lastly, activation of acetylcholinesterase which led to more breakdown of the acetylcholine, the important neurotransmitter for the neuron. All consequences ultimately led to an impairment in cognitive memory. These modifications occur due to Al being a powerful cholinotoxin that influences the blood-brain barrier, causing changes in noradrenaline and cholinergic neurotransmission (Yokel 2000), whereas D-gal enhances AchE activity in the brain of rats (Rodrigues et al. 2017).
Concatenation of molecular docking and molecular simulation of BACE-1, γ-secretase targeted ligands: in pursuit of Alzheimer’s treatment
Published in Annals of Medicine, 2021
Nasimudeen R. Jabir, Md. Tabish Rehman, Khadeejah Alsolami, Shazi Shakil, Torki A. Zughaibi, Raed F. Alserihi, Mohd. Shahnawaz Khan, Mohamed F. AlAjmi, Shams Tabrez
In contrast to studies on acetylcholinesterase inhibitors, the elucidation of AD therapeutic potential of BACE-1 and γ-secretase are inadequate because of the lack of potent and selective chemical probes [19]. These lacunae indicate the need to develop an efficient and specific inhibitor targeting these enzymes. Over the past two decades, pharmacological design and development of BACE-1 inhibitors with favorable physicochemical properties along with BBB permeability have undergone multiple challenging phases [55,56]. Ongoing experimental trials showed promising results of pharmacological BACE-1 inhibitors, MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520, and are being intensively pursued as a therapeutic approach to treat AD patients [38]. Despite the high failure of lead drug candidates targeting BACE-1, this therapeutic strategy is not withdrawn, as it represents a pathologic mechanism-based treatment for AD. A recent study also encouraged novel compounds with an ultra-APP selectivity resulting in BACE-1 inhibitory effect [57]. Besides, BACE-1 inhibition has also been suggested as a combination therapy, a more effective way of improving cognition in AD [55]. In addition, γ-secretase inhibitors viz. avagacestat and semagacestat have undergone late-stage clinical trials for AD (phase II and phase III, respectively) [19]. However, these inhibitors have shown several side effects throughout the clinical trials [19].