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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).
Hum. (περὶ χυμῶν, de humoribus)
Published in Elizabeth M. Craik, The ‘Hippocratic’ Corpus, 2014
Unsurprisingly, in view of the aphoristic expression favoured in On Humours, there are similarities also with the content of Aphorisms. While these similarities to some extent reflect common lore, it appears from the ordering in Aphorisms that some of the material there may be drawn directly from On Humours. There is one peculiar collocation (Hum. 6 ~ Aph. 1. 19–1. 24 [4. 468–470 L.]). The view that climate and natural phenomena are determinants of human health is seen above all in Airs, Waters and Places (Hum. 12 ~ Aer. 7 and 9 [2. 36–38 L.]). And the reasoning which underlies Erotian’s classification is evident in that stress on the importance of particular signs mirrors the content of the prognostic works (Hum. 3 ~ Prog. 11 [2. 138 L.]; 4 ~ Prorrh. 1. 39 [5. 520 L.]). There are somewhat more elusive, or allusive, points in common with the surgical works (Hum. 4 ~ Artic. 53 [4.236 L.]), also with the more speculative ‘scientific’ works, relating to dominant bodily components, such as On Winds and On Ancient Medicine; also with certain nosological or therapeutic works, such as On Acute Diseases. In addition, the ideas of Demokritos are clearly familiar and some concerns are shared with Aristotle who gives an explicit explanation of the terms πέπονα and ὠμά as used in On Humours (Arist. Meteorologica 380a; for other common elements see GA 783b25–26 and PA 678a11–13).
Memorcise and Alzheimer’s disease
Published in The Physician and Sportsmedicine, 2018
Paul D. Loprinzi, Emily Frith, Pamela Ponce
The initial step in the production of Aβ is cleaving the large APP by beta- and gamma-secretase proteases [30]. The primary β-secretase enzyme is β-site APP cleaving enzyme (BACE1). Deletion of BACE1 reduces Aβ levels and may help to prevent memory decline [31]. Gamma-secretase also plays a critical role in the generation of Aβ by interacting with four core proteins, namely presenilin, nicastrin, aph-1, and pen-2 [32], which elevate levels of Aβ. Increases in Aβ exacerbate disrupted cholesterol homeostasis via Aβ’s direct binding affinity for lipid bilayers, altering membrane fluidity [33] and perturbing ion channel function and Ca2+ homeostasis [34]. As noted above, traditionally, extracellular Aβ has been implicated in the pathophysiology of AD. More recent discussions implicate intraneuronal Aβ accumulation also contributing to the synapse pathology of AD, particularly via altered morphology of neurites and synapses [35,36]. These proteins exhibit prion-like properties [37,38], with the intracellular transfer of misfolded proteins inducing an aggregated state [39].
The relationship between cholesterol level and Alzheimer’s disease-associated APP proteolysis/Aβ metabolism
Published in Nutritional Neuroscience, 2019
Chaoqun Wang, Yikai Shou, Jie Pan, Yue Du, Cuiqing Liu, Huanhuan Wang
γ-secretase of APP is composed of four integral membrane proteins, presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin, Aph-1, and Pen-2. During the assemblage and maturation of this protein complex, presenilin is cleaved into two subunits, an N-terminal fragment and CTF, each of which contributes one transmembrane aspartate to the active site.76 De Strooper et al. found that the Aβ level decreased to one-fifth of that in controls upon knockout of PS1, suggesting that PS1 plays a leading role in the proteolysis of C99.77
The Notch pathway: a novel therapeutic target for cardiovascular diseases?
Published in Expert Opinion on Therapeutic Targets, 2019
Giorgio Aquila, Aleksandra Kostina, Francesco Vieceli Dalla Sega, Eugeniy Shlyakhto, Anna Kostareva, Luisa Marracino, Roberto Ferrari, Paola Rizzo, Anna Malaschicheva
The interaction between the Notch receptor on one cell and the ligand on the adjacent cell (trans-interaction) results in conformational changes of the receptor extracellular domain exposing a motif that is cleaved by ADAM (A Disintegrin And Metalloproteinase) (S2 cleavage site) [4]. The S2 cleavage creates membrane-tethered intermediate called Notch extracellular truncation (NEXT) that is substrate for γ-secretase protease complex, containing presenilin1, presenilin2, Pen-2, Aph-1 and nicastrin [5,6]. The γ-secretase cleaves the Notch receptors at the two distinct sites, S3/S4, and releases NICD, which translocates to the nucleus to regulate gene transcription [7]. Nuclear Notch signals cause changes in gene expression mediated by the transcription factor CSL (an acronym for CBF-1/RBP-Jκ in Homo sapiens/Mus musculus, respectively, Suppressor of Hairless in Drosophila melanogaster, Lag-1 in Caenorhabditis elegans). In the absence of NICD, CSL is bound by corepressor proteins, such as SMRT (NcoR) and SHRP (MINT/SPEN), and inhibits the transcription of target genes by recruiting histone deacetylases [8]. NICD/CSL binding displaces corepressor complexes and allows recruitment of the transcriptional coactivator Mastermind-Like-1 (MAML) and histone acetyltransferases such as p300 [9]. Formation of CSL/NICD/MAML complex results in direct transcriptional activation of target genes (Figure 1). Recent data also show a direct implication of NICD in chromatin remodeling [10,11]. In cancer and immune system, a Notch signaling active in the cytoplasm (referred to as ‘noncanonical’ Notch signaling to distinguish it from the canonical, nuclear Notch signaling) has been described [12]. Non-canonical Notch signaling occurs without CSL involvement and depends on interactions between the NICD and pathways such as mammalian target of the rapamycin 2 complex (mTORC2)/Akt, Wnt/β-catenin and Nuclear Factor kappa B (NF-κB)/AKK-α/AKK-β [12]. Non-canonical Notch signaling has also been observed in mitochondria where interactions between Notch and PTEN-induced kinase 1 (PINK1) promote cell survival by activating the mTORC2/Akt pathway. Notch signaling can be also triggered by ligands other than Jagged/Dll. These alternative ligands include F3/contactin, Delta-like 1–2 (DLK1-2) and epidermal growth factor domain 7 (EGFL7) and seem to influence Notch signaling by competing with Jagged/Dll for Notch receptor binding [12,13]. Notch activation, by either mechanisms described above, influences cell proliferation, apoptosis, and differentiation [13]. More recently, a role of Notch in the regulation of autophagy has been reported in cancer [14] and immune cells [15].