Counteracting role of nuclear factor erythroid 2-related factor 2 pathway in Alzheimer's disease - 28/08/20
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Graphical abstract |
Highlights |
• | In ageing and neurodegeneration, activity of Nrf2 is compromised, specially in AD. |
• | The Keap-1-Nrf2-ARE pathway in AD. |
• | Nrf2 regulation is achieved by various pathways both in cytoplasm and nucleus |
• | The various pathways involved in positive Nrf2 modulation are PI3K, MAPKs and CREB. |
• | The GSK-3β,NF-Kb, JAK-STAT,TNF-α are potential therapeutic targets in AD. |
Abstract |
A salient pathological features in Alzheimer’s disease includes redox impairment and neuroinflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) and Nuclear factor kappa B (NF-ҡB) are the two key transcription factors that regulate cellular responses to redox impairment and neuroinflammation respectively. An effective way to confer neuroprotection in central nervous system (CNS) is the activation of a transcription factor i.e Nuclear factor erythroid 2-related factor 2 (Nrf2). An enhancer element known as Antioxidant Response Element (ARE) mediates the expression of phase II detoxification enzymes. Nrf2 is a nuclear transcription factor that binds to ARE thereby transcribing expression of several antioxidant genes. Kelch ECH associating protein-1 (Keap1), a culin 3-based E3 ligase, polyubiquitinates Nrf2 and targets it for its degradation. Disruption in the interaction between Keap1/Nrf2 can increase the brain’s endogenous antioxidant capacity and thereby responsible for cell defence against oxidative stress and neuroinflammation in Alzheimer’s disease (AD). The current review discusses about Keap1-Nrf2-ARE structure and function with special emphasis on the various pathways involved in positive and negative modulation of Nrf2, namely Phosphoinositide 3- kinase (PI3K), Glycogen synthase kinase-3β (GSK-3β), Nuclear factor kappa-b (NF-ҡb), Janus kinase/signal transducer and activator of transcription (JAK-STAT),Tumour Necrosis Factor- α (TNF-α), p38Mitogen-activated protein kinases (p38MAPK), Cyclic AMP response element binding protein (CREB) and intrinsic & extrinsic apoptotic pathway. Furthermore, this review highlights the miscellaneous Nrf2 activators as promising therapeutic agents for slowingdown the progression of AD.
El texto completo de este artículo está disponible en PDF.Abbreviations : AD, Apaf-1, APP, ARE, Aβ, Bcl-2, BPD, CNC, CNS, COX-2, CREB, GCL, GCS, GSH, GSK-3β, GST, HD, HO-1, HSP32, IL, IRI, JAK-STAT, Keap1, MAPKs, NDDs, NF-Kb, NFT, NQO1, Nrf2, PD, PI3K, RNS, ROS, TNF-α
Keywords : Alzheimer’s disease, Neuroinflammation, Redox-regulated transcription factor, Nrf2 activators, Apoptotic pathway
Esquema
Vol 129
Artículo 110373- septembre 2020 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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