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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).
Micronutrients in the Prevention and Improvement of the Standard Therapy for Alzheimer’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Increased oxidative stress increases the production and accumulation of β-amyloids in neurons. Indeed, it has been reported that increased oxidative events can accelerate the intracellular buildup of β-amyloids in neurons.188 Studies showed that membranes containing oxidatively damaged phospholipids accumulated of β-amyloids faster than membranes containing only unoxidized saturated phospholipids.189 The rate of cleavage of APP to Aβ1-42 was increased in a transgenic AD mouse model lacking cytoplasmic superoxide dismutase-1 (SOD-1) relative to control mice, implying that increased oxidative events can promote the production of Aβ1-42 peptides.190 Furthermore, 4-hydroxynonenal (HNE), a product of lipid peroxidation, increased γ-secretase activity and Aβ1-42 assembly in neurons.191 HNE modified the γ-secretase substrate receptor, nicastrin, in neurons from patients with AD. Such modification of nicastrin heightened its binding to the γ-secretase substrate APP. The levels of HNE-nicastrin were associated with increased γ-secretase activity and Aβ plaque deposition.191,192
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].
An update on the pathogenesis of hidradenitis suppurativa: implications for therapy
Published in Expert Review of Clinical Immunology, 2018
Deborah Negus, Christine Ahn, William Huang
Most cases of HS occur in sporadic forms and familial forms. Our understanding of the genetic basis for HS has continued to evolve over time. Initially, a genetic component was suspected due to many patients reporting a positive family history of HS. Studies to quantify this revealed up to 40% of patients had a positive history of HS in a first-degree relative. It was not until 2006 when the first genetic locus thought to be responsible for HS was identified [15]. In this genome-wide scan of four generations of a Chinese family, the responsible gene was mapped to chromosome 1p21.1–1q25.3 [15]. Since this study, additional mutations have been identified with advances in genetic studies, particularly exome sequencing. Since the initial identification to chromosome 1p21.1–1q25.3, heterozygous mutations in the γ-secretase genes nicastrin (NCSTN), presenilin enhancer 2 (PSENEN), and presenilin (encoded by PSEN1 and PSEN2) have been identified [16–21]. These mutations are likely responsible for a small proportion of cases of HS, estimated to be less than 7%. Initially, mutations in NCSTN, PSENEN, and PSEN1 were reported in multiple Chinese families, although mutations have now been reported in British, Japanese, and French families as well as in several sporadic cases [21,22]. There is still ongoing debate on the role of these mutations in the development of HS, as some believe that a γ-secretase is insufficient to produce the HS clinical phenotype. One report to support this suggestion is an individual with a nonsense NCSTN mutation with both a brother and sister who harbor the mutation, with one sibling demonstrating no evidence of HS during her lifetime [23].
A review of IL-36: an emerging therapeutic target for inflammatory dermatoses
Published in Journal of Dermatological Treatment, 2022
Jonwei Hwang, Jonathan Rick, Jennifer Hsiao, Vivian Y. Shi
Preclinical data regarding IL-36 in HS is sparse, this is likely because the first HS mouse model was reportedly established in a 2020 study. Nicastrin (NCSTN), the most commonly mutated gene in familial HS, was knocked down leading to mice displaying clinical hallmarks of disease, such as keratinization, keratotic plug formation, and hair follicle inflammation. IL-36α expression was markedly increased starting from postnatal day 0 and significantly higher than wild-type controls (84). However, the impact of these findings is naturally limited by the uniqueness of this genetic model, and it is unclear if this is a hallmark of true HS inflammation.