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Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia
Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease caused by CAG repeats in exon 1 of the HTT gene. A hallmark of HD along with other psychiatric and neurodegenerative diseases is alteration in the neuronal circuitry and synaptic loss. Microglia and peripheral inn...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319581/ https://www.ncbi.nlm.nih.gov/pubmed/37415834 http://dx.doi.org/10.3389/fnmol.2023.1191324 |
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author | Gasser, Julien Gillet, Gaelle Valadas, Jorge S. Rouvière, Laura Kotian, Apoorva Fan, Wenqiang Keaney, James Kadiu, Irena |
author_facet | Gasser, Julien Gillet, Gaelle Valadas, Jorge S. Rouvière, Laura Kotian, Apoorva Fan, Wenqiang Keaney, James Kadiu, Irena |
author_sort | Gasser, Julien |
collection | PubMed |
description | Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease caused by CAG repeats in exon 1 of the HTT gene. A hallmark of HD along with other psychiatric and neurodegenerative diseases is alteration in the neuronal circuitry and synaptic loss. Microglia and peripheral innate immune activation have been reported in pre-symptomatic HD patients; however, what “activation” signifies for microglial and immune function in HD and how it impacts synaptic health remains unclear. In this study we sought to fill these gaps by capturing immune phenotypes and functional activation states of microglia and peripheral immunity in the R6/2 model of HD at pre-symptomatic, symptomatic and end stages of disease. These included characterizations of microglial phenotypes at single cell resolution, morphology, aberrant functions such as surveillance and phagocytosis and their impact on synaptic loss in vitro and ex vivo in R6/2 mouse brain tissue slices. To further understand how relevant the observed aberrant microglial behaviors are to human disease, transcriptomic analysis was performed using HD patient nuclear sequencing data and functional assessments were conducted using induced pluripotent stem cell (iPSC)-derived microglia. Our results show temporal changes in brain infiltration of peripheral lymphoid and myeloid cells, increases in microglial activation markers and phagocytic functions at the pre-symptomatic stages of disease. Increases in microglial surveillance and synaptic uptake parallel significant reduction of spine density in R6/2 mice. These findings were mirrored by an upregulation of gene signatures in the endocytic and migratory pathways in disease-associated microglial subsets in human HD brains, as well as increased phagocytic and migratory functions of iPSC-derived HD microglia. These results collectively suggest that targeting key and specific microglial functions related to synaptic surveillance and pruning may be therapeutically beneficial in attenuating cognitive decline and psychiatric aspects of HD. |
format | Online Article Text |
id | pubmed-10319581 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103195812023-07-06 Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia Gasser, Julien Gillet, Gaelle Valadas, Jorge S. Rouvière, Laura Kotian, Apoorva Fan, Wenqiang Keaney, James Kadiu, Irena Front Mol Neurosci Molecular Neuroscience Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease caused by CAG repeats in exon 1 of the HTT gene. A hallmark of HD along with other psychiatric and neurodegenerative diseases is alteration in the neuronal circuitry and synaptic loss. Microglia and peripheral innate immune activation have been reported in pre-symptomatic HD patients; however, what “activation” signifies for microglial and immune function in HD and how it impacts synaptic health remains unclear. In this study we sought to fill these gaps by capturing immune phenotypes and functional activation states of microglia and peripheral immunity in the R6/2 model of HD at pre-symptomatic, symptomatic and end stages of disease. These included characterizations of microglial phenotypes at single cell resolution, morphology, aberrant functions such as surveillance and phagocytosis and their impact on synaptic loss in vitro and ex vivo in R6/2 mouse brain tissue slices. To further understand how relevant the observed aberrant microglial behaviors are to human disease, transcriptomic analysis was performed using HD patient nuclear sequencing data and functional assessments were conducted using induced pluripotent stem cell (iPSC)-derived microglia. Our results show temporal changes in brain infiltration of peripheral lymphoid and myeloid cells, increases in microglial activation markers and phagocytic functions at the pre-symptomatic stages of disease. Increases in microglial surveillance and synaptic uptake parallel significant reduction of spine density in R6/2 mice. These findings were mirrored by an upregulation of gene signatures in the endocytic and migratory pathways in disease-associated microglial subsets in human HD brains, as well as increased phagocytic and migratory functions of iPSC-derived HD microglia. These results collectively suggest that targeting key and specific microglial functions related to synaptic surveillance and pruning may be therapeutically beneficial in attenuating cognitive decline and psychiatric aspects of HD. Frontiers Media S.A. 2023-06-20 /pmc/articles/PMC10319581/ /pubmed/37415834 http://dx.doi.org/10.3389/fnmol.2023.1191324 Text en Copyright © 2023 Gasser, Gillet, Valadas, Rouvière, Kotian, Fan, Keaney and Kadiu. 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 | Molecular Neuroscience Gasser, Julien Gillet, Gaelle Valadas, Jorge S. Rouvière, Laura Kotian, Apoorva Fan, Wenqiang Keaney, James Kadiu, Irena Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia |
title | Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia |
title_full | Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia |
title_fullStr | Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia |
title_full_unstemmed | Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia |
title_short | Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia |
title_sort | innate immune activation and aberrant function in the r6/2 mouse model and huntington’s disease ipsc-derived microglia |
topic | Molecular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319581/ https://www.ncbi.nlm.nih.gov/pubmed/37415834 http://dx.doi.org/10.3389/fnmol.2023.1191324 |
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