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BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias
ITM2B/BRI2 mutations cause familial forms of Alzheimer’s disease (AD)-related dementias by disrupting BRI2’s protein function and leading to the accumulation of amyloidogenic peptides. Although typically studied in neurons, our findings show that BRI2 is highly expressed in microglia, which are cruc...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Cold Spring Harbor Laboratory
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312752/ https://www.ncbi.nlm.nih.gov/pubmed/37398330 http://dx.doi.org/10.1101/2023.06.14.544924 |
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author | Yin, Tao D’Adamio, Luciano |
author_facet | Yin, Tao D’Adamio, Luciano |
author_sort | Yin, Tao |
collection | PubMed |
description | ITM2B/BRI2 mutations cause familial forms of Alzheimer’s disease (AD)-related dementias by disrupting BRI2’s protein function and leading to the accumulation of amyloidogenic peptides. Although typically studied in neurons, our findings show that BRI2 is highly expressed in microglia, which are crucial in AD pathogenesis due to the association of variants in the microglial gene TREM2 with increased AD risk. Our single-cell RNAseq (scRNAseq) analysis revealed a microglia cluster that depends on a Trem2 activity that is inhibited by Bri2, pointing to a functional interaction between Itm2b/Bri2 and Trem2. Given that the AD-related Amyloid-β Precursor protein (APP) and TREM2 undergo similar proteolytic processing, and that BRI2 inhibits APP processing, we hypothesized that BRI2 may also regulate TREM2 processing. We found that BRI2 interacts with Trem2 and inhibits its processing by α-secretase in transfected cells. In mice lacking Bri2 expression, we observed increased central nervous system (CNS) levels of Trem2-CTF and sTrem2, which are the products of α-secretase processing of Trem2, indicating increased Trem2 processing by α-secretase in vivo. Reducing Bri2 expression only in microglia resulted in increased sTrem2 levels, suggesting a cell-autonomous effect of Bri2 on α-secretase processing of Trem2. Our study reveals a previously unknow role of BRI2 in regulating TREM2-related neurodegenerative mechanisms. The ability of BRI2 to regulate the processing of both APP and TREM2, combined with its cell-autonomous role in neurons and microglia, makes it a promising candidate for the development of AD and AD-related dementias therapeutics. |
format | Online Article Text |
id | pubmed-10312752 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-103127522023-07-01 BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias Yin, Tao D’Adamio, Luciano bioRxiv Article ITM2B/BRI2 mutations cause familial forms of Alzheimer’s disease (AD)-related dementias by disrupting BRI2’s protein function and leading to the accumulation of amyloidogenic peptides. Although typically studied in neurons, our findings show that BRI2 is highly expressed in microglia, which are crucial in AD pathogenesis due to the association of variants in the microglial gene TREM2 with increased AD risk. Our single-cell RNAseq (scRNAseq) analysis revealed a microglia cluster that depends on a Trem2 activity that is inhibited by Bri2, pointing to a functional interaction between Itm2b/Bri2 and Trem2. Given that the AD-related Amyloid-β Precursor protein (APP) and TREM2 undergo similar proteolytic processing, and that BRI2 inhibits APP processing, we hypothesized that BRI2 may also regulate TREM2 processing. We found that BRI2 interacts with Trem2 and inhibits its processing by α-secretase in transfected cells. In mice lacking Bri2 expression, we observed increased central nervous system (CNS) levels of Trem2-CTF and sTrem2, which are the products of α-secretase processing of Trem2, indicating increased Trem2 processing by α-secretase in vivo. Reducing Bri2 expression only in microglia resulted in increased sTrem2 levels, suggesting a cell-autonomous effect of Bri2 on α-secretase processing of Trem2. Our study reveals a previously unknow role of BRI2 in regulating TREM2-related neurodegenerative mechanisms. The ability of BRI2 to regulate the processing of both APP and TREM2, combined with its cell-autonomous role in neurons and microglia, makes it a promising candidate for the development of AD and AD-related dementias therapeutics. Cold Spring Harbor Laboratory 2023-06-14 /pmc/articles/PMC10312752/ /pubmed/37398330 http://dx.doi.org/10.1101/2023.06.14.544924 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Yin, Tao D’Adamio, Luciano BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias |
title | BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias |
title_full | BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias |
title_fullStr | BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias |
title_full_unstemmed | BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias |
title_short | BRI2-mediated regulation of TREM2 processing in microglia and its potential implications for Alzheimer’s disease and related dementias |
title_sort | bri2-mediated regulation of trem2 processing in microglia and its potential implications for alzheimer’s disease and related dementias |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312752/ https://www.ncbi.nlm.nih.gov/pubmed/37398330 http://dx.doi.org/10.1101/2023.06.14.544924 |
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