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Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease

BACKGROUND: Alzheimer’s disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers...

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Autores principales: Wang, Xiang, Wang, Yu, Zhu, Yiyi, Yan, Luxia, Zhao, Liandong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890185/
https://www.ncbi.nlm.nih.gov/pubmed/31819374
http://dx.doi.org/10.2147/DDDT.S233283
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author Wang, Xiang
Wang, Yu
Zhu, Yiyi
Yan, Luxia
Zhao, Liandong
author_facet Wang, Xiang
Wang, Yu
Zhu, Yiyi
Yan, Luxia
Zhao, Liandong
author_sort Wang, Xiang
collection PubMed
description BACKGROUND: Alzheimer’s disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aβ(1-42)-injected mice (Aβ(1-42)-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deficits. MATERIALS AND METHODS: AD model mice were manufactured through intracerebroventricular injection of Aβ(1-42). Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot. RESULTS: The results demonstrated that FTS could prevent Aβ(1-42) to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aβ(1-42)-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aβ(1-42)-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aβ, which is the underlying molecular mechanism. CONCLUSION: In conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.
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spelling pubmed-68901852019-12-09 Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease Wang, Xiang Wang, Yu Zhu, Yiyi Yan, Luxia Zhao, Liandong Drug Des Devel Ther Original Research BACKGROUND: Alzheimer’s disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aβ(1-42)-injected mice (Aβ(1-42)-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deficits. MATERIALS AND METHODS: AD model mice were manufactured through intracerebroventricular injection of Aβ(1-42). Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot. RESULTS: The results demonstrated that FTS could prevent Aβ(1-42) to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aβ(1-42)-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aβ(1-42)-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aβ, which is the underlying molecular mechanism. CONCLUSION: In conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD. Dove 2019-11-29 /pmc/articles/PMC6890185/ /pubmed/31819374 http://dx.doi.org/10.2147/DDDT.S233283 Text en © 2019 Wang et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Wang, Xiang
Wang, Yu
Zhu, Yiyi
Yan, Luxia
Zhao, Liandong
Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease
title Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease
title_full Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease
title_fullStr Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease
title_full_unstemmed Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease
title_short Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer’s Disease
title_sort neuroprotective effect of s-trans, trans-farnesylthiosalicylic acid via inhibition of ras/erk pathway for the treatment of alzheimer’s disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890185/
https://www.ncbi.nlm.nih.gov/pubmed/31819374
http://dx.doi.org/10.2147/DDDT.S233283
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