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Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA

Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP)...

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Autores principales: Sato, Kaoru, Takayama, Ken-ichi, Hashimoto, Makoto, Inoue, Satoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261399/
https://www.ncbi.nlm.nih.gov/pubmed/35822056
http://dx.doi.org/10.3389/fragi.2021.721579
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author Sato, Kaoru
Takayama, Ken-ichi
Hashimoto, Makoto
Inoue, Satoshi
author_facet Sato, Kaoru
Takayama, Ken-ichi
Hashimoto, Makoto
Inoue, Satoshi
author_sort Sato, Kaoru
collection PubMed
description Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP), it has been assumed that misfolding of Aβ plays a crucial role in the AD pathogenesis. Additionally, extra copies of the APP gene caused by chromosomal duplication in patients with Down syndrome can promote AD pathogenesis, indicating the pathological involvement of the APP gene dose in AD. Furthermore, increased APP expression due to locus duplication and promoter mutation of APP has been found in familial AD. Given this background, we aimed to summarize the mechanism underlying the upregulation of APP expression levels from a cutting-edge perspective. We first reviewed the literature relevant to this issue, specifically focusing on the transcriptional regulation of APP by transcription factors that bind to the promoter/enhancer regions. APP expression is also regulated by growth factors, cytokines, and hormone, such as androgen. We further evaluated the possible involvement of post-transcriptional regulators of APP in AD pathogenesis, such as RNA splicing factors. Indeed, alternative splicing isoforms of APP are proposed to be involved in the increased production of Aβ. Moreover, non-coding RNAs, including microRNAs, post-transcriptionally regulate the APP expression. Collectively, elucidation of the novel mechanisms underlying the upregulation of APP would lead to the development of clinical diagnosis and treatment of AD.
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spelling pubmed-92613992022-07-11 Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA Sato, Kaoru Takayama, Ken-ichi Hashimoto, Makoto Inoue, Satoshi Front Aging Aging Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP), it has been assumed that misfolding of Aβ plays a crucial role in the AD pathogenesis. Additionally, extra copies of the APP gene caused by chromosomal duplication in patients with Down syndrome can promote AD pathogenesis, indicating the pathological involvement of the APP gene dose in AD. Furthermore, increased APP expression due to locus duplication and promoter mutation of APP has been found in familial AD. Given this background, we aimed to summarize the mechanism underlying the upregulation of APP expression levels from a cutting-edge perspective. We first reviewed the literature relevant to this issue, specifically focusing on the transcriptional regulation of APP by transcription factors that bind to the promoter/enhancer regions. APP expression is also regulated by growth factors, cytokines, and hormone, such as androgen. We further evaluated the possible involvement of post-transcriptional regulators of APP in AD pathogenesis, such as RNA splicing factors. Indeed, alternative splicing isoforms of APP are proposed to be involved in the increased production of Aβ. Moreover, non-coding RNAs, including microRNAs, post-transcriptionally regulate the APP expression. Collectively, elucidation of the novel mechanisms underlying the upregulation of APP would lead to the development of clinical diagnosis and treatment of AD. Frontiers Media S.A. 2021-08-11 /pmc/articles/PMC9261399/ /pubmed/35822056 http://dx.doi.org/10.3389/fragi.2021.721579 Text en Copyright © 2021 Sato, Takayama, Hashimoto and Inoue. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Aging
Sato, Kaoru
Takayama, Ken-ichi
Hashimoto, Makoto
Inoue, Satoshi
Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA
title Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA
title_full Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA
title_fullStr Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA
title_full_unstemmed Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA
title_short Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA
title_sort transcriptional and post-transcriptional regulations of amyloid-β precursor protein (app) mrna
topic Aging
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261399/
https://www.ncbi.nlm.nih.gov/pubmed/35822056
http://dx.doi.org/10.3389/fragi.2021.721579
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