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Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant
The R47H variant of the Triggering-Receptor-Expressed on Myeloid cells 2 (TREM2) increases the risk of Alzheimer’s disease (AD). Mutagenesis of exon 2 in Knock-in (KI) mouse models of the R47H variant introduced a cryptic splice site, leading to nonsense mediated decay. Since haploinsufficiency does...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058057/ https://www.ncbi.nlm.nih.gov/pubmed/32139718 http://dx.doi.org/10.1038/s41598-020-60800-1 |
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author | Tambini, Marc D. D’Adamio, Luciano |
author_facet | Tambini, Marc D. D’Adamio, Luciano |
author_sort | Tambini, Marc D. |
collection | PubMed |
description | The R47H variant of the Triggering-Receptor-Expressed on Myeloid cells 2 (TREM2) increases the risk of Alzheimer’s disease (AD). Mutagenesis of exon 2 in Knock-in (KI) mouse models of the R47H variant introduced a cryptic splice site, leading to nonsense mediated decay. Since haploinsufficiency does not model Trem2-R47H function, a new rat KI model, the Trem2(R47H) KI rat was created. Human Aβ has higher propensity to form toxic Aβ species, which are considered the main pathogenic entity in AD, as compared to rodent Aβ, the rat Amyloid Precursor Protein (App) gene was mutated to produce human Aβ. Trem2 splicing and expression was measured in Trem2(R47H) KI rat brains and microglia by qualitative and quantitative RT-PCR. Trem2 levels and Trem2 processing was assessed by Western analysis. APP metabolite levels were determined by enzyme-linked immunosorbent assay (ELISA), for Human Aβ and soluble APP, and Western analysis, for full length APP, βCTF and αCTF. Trem2 expression and Trem2 levels are unchanged in Trem2(R47H) KI rats. The artifactual splicing seen in KI mouse models is not present; additionally, two novel isoforms of rat Trem2 are described. Trem2(R47H) rat brains have lower human Aβ38, sAPPα and sAPPβ levels. Thus, Trem2(R47H) KI rats may prove valuable to define pathogenic mechanisms triggered by the Trem2 R47H variant, including those mediated by toxic species of human Aβ peptides. |
format | Online Article Text |
id | pubmed-7058057 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70580572020-03-12 Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant Tambini, Marc D. D’Adamio, Luciano Sci Rep Article The R47H variant of the Triggering-Receptor-Expressed on Myeloid cells 2 (TREM2) increases the risk of Alzheimer’s disease (AD). Mutagenesis of exon 2 in Knock-in (KI) mouse models of the R47H variant introduced a cryptic splice site, leading to nonsense mediated decay. Since haploinsufficiency does not model Trem2-R47H function, a new rat KI model, the Trem2(R47H) KI rat was created. Human Aβ has higher propensity to form toxic Aβ species, which are considered the main pathogenic entity in AD, as compared to rodent Aβ, the rat Amyloid Precursor Protein (App) gene was mutated to produce human Aβ. Trem2 splicing and expression was measured in Trem2(R47H) KI rat brains and microglia by qualitative and quantitative RT-PCR. Trem2 levels and Trem2 processing was assessed by Western analysis. APP metabolite levels were determined by enzyme-linked immunosorbent assay (ELISA), for Human Aβ and soluble APP, and Western analysis, for full length APP, βCTF and αCTF. Trem2 expression and Trem2 levels are unchanged in Trem2(R47H) KI rats. The artifactual splicing seen in KI mouse models is not present; additionally, two novel isoforms of rat Trem2 are described. Trem2(R47H) rat brains have lower human Aβ38, sAPPα and sAPPβ levels. Thus, Trem2(R47H) KI rats may prove valuable to define pathogenic mechanisms triggered by the Trem2 R47H variant, including those mediated by toxic species of human Aβ peptides. Nature Publishing Group UK 2020-03-05 /pmc/articles/PMC7058057/ /pubmed/32139718 http://dx.doi.org/10.1038/s41598-020-60800-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Tambini, Marc D. D’Adamio, Luciano Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant |
title | Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant |
title_full | Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant |
title_fullStr | Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant |
title_full_unstemmed | Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant |
title_short | Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer’s Risk Variant |
title_sort | trem2 splicing and expression are preserved in a human aβ-producing, rat knock-in model of trem2-r47h alzheimer’s risk variant |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058057/ https://www.ncbi.nlm.nih.gov/pubmed/32139718 http://dx.doi.org/10.1038/s41598-020-60800-1 |
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