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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1191324/full |
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| author | Julien Gasser Gaelle Gillet Jorge S. Valadas Laura Rouvière Apoorva Kotian Wenqiang Fan James Keaney Irena Kadiu |
| author_facet | Julien Gasser Gaelle Gillet Jorge S. Valadas Laura Rouvière Apoorva Kotian Wenqiang Fan James Keaney Irena Kadiu |
| author_sort | Julien Gasser |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T04:20:32Z |
| format | Article |
| id | doaj.art-36f81fae85e74d06aa8c531767ce20bb |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-13T04:20:32Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-36f81fae85e74d06aa8c531767ce20bb2023-06-20T10:17:04ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-06-011610.3389/fnmol.2023.11913241191324Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microgliaJulien Gasser0Gaelle Gillet1Jorge S. Valadas2Laura Rouvière3Apoorva Kotian4Wenqiang Fan5James Keaney6Irena Kadiu7Neuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, BelgiumNeuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, BelgiumNeuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, BelgiumNeuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, BelgiumDevelopment Science, UCB Biopharma SRL, Slough, United KingdomNeuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, BelgiumNeuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, BelgiumNeuroinflammation Focus Area, Neuroscience Research, UCB Biopharma SRL, Braine-l’Alleud, BelgiumHuntington’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.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1191324/fullmicrogliaphagocytosismigrationneuroinflammationHuntington’s diseasedendritic spines |
| spellingShingle | Julien Gasser Gaelle Gillet Jorge S. Valadas Laura Rouvière Apoorva Kotian Wenqiang Fan James Keaney Irena Kadiu Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia Frontiers in Molecular Neuroscience microglia phagocytosis migration neuroinflammation Huntington’s disease dendritic spines |
| 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 | microglia phagocytosis migration neuroinflammation Huntington’s disease dendritic spines |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1191324/full |
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