microRNA-132 regulates gene expression programs involved in microglial homeostasis

Hannah Walgrave; Amber Penning; Giorgia Tosoni; Sarah Snoeck; Kristofer Davie; Emma Davis; Leen Wolfs; Annerieke Sierksma; Mayte Mars; Taofeng Bu; Nicola Thrupp; Lujia Zhou; Diederik Moechars; Renzo Mancuso; Mark Fiers; Andrew J. M. Howden; Bart De Strooper; Evgenia Salta

doi:10.1016/j.isci.2023.106829

microRNA-132 regulates gene expression programs involved in microglial homeostasis

Hannah Walgrave, Amber Penning, Giorgia Tosoni, Sarah Snoeck, Kristofer Davie, Emma Davis, Leen Wolfs, Annerieke Sierksma, Mayte Mars, Taofeng Bu, Nicola Thrupp, Lujia Zhou, Diederik Moechars, Renzo Mancuso, Mark Fiers, Andrew J. M. Howden, Bart De Strooper (Lead / Corresponding author), Evgenia Salta (Lead / Corresponding author)

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Abstract

microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.

Original language	English
Article number	106829
Number of pages	32
Journal	iScience
Volume	26
Issue number	6
Early online date	6 May 2023
DOIs	https://doi.org/10.1016/j.isci.2023.106829
Publication status	Published - 16 Jun 2023

Keywords

Molecular biology
Neuroscience
Omics

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2023.106829Licence: CC BY

Final Published VersionFinal published version, 5.13 MBLicence: CC BY

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Walgrave, H., Penning, A., Tosoni, G., Snoeck, S., Davie, K., Davis, E., Wolfs, L., Sierksma, A., Mars, M., Bu, T., Thrupp, N., Zhou, L., Moechars, D., Mancuso, R., Fiers, M., Howden, A. J. M., De Strooper, B., & Salta, E. (2023). microRNA-132 regulates gene expression programs involved in microglial homeostasis. iScience, 26(6), Article 106829. https://doi.org/10.1016/j.isci.2023.106829

@article{643b9faf07b7427ea9db5f64329d7707,

title = "microRNA-132 regulates gene expression programs involved in microglial homeostasis",

abstract = "microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.",

keywords = "Molecular biology, Neuroscience, Omics",

author = "Hannah Walgrave and Amber Penning and Giorgia Tosoni and Sarah Snoeck and Kristofer Davie and Emma Davis and Leen Wolfs and Annerieke Sierksma and Mayte Mars and Taofeng Bu and Nicola Thrupp and Lujia Zhou and Diederik Moechars and Renzo Mancuso and Mark Fiers and Howden, {Andrew J. M.} and {De Strooper}, Bart and Evgenia Salta",

note = "Funding Information: We thank V{\'e}ronique Hendrickx and Jonas Verwaeren for animal husbandry; and Katrien Horr{\'e}, Katleen Craessaerts, An Snellinx, Elke Vanden Eynde and Tom Jaspers for technical assistance. In addition, we thank Nicola Fattorelli, Pranav Preman, and Anna Martinez Muriana for scientific discussions and critical feedback. The Thy1-YFP mice were a kind gift from Lieve Moons and Lies De Groef (KU Leuven). Part of the schematics in figures was created with BioRender.com. H.W. is a Fonds voor Wetenschappelijk Onderzoek – Vlaanderen (FWO) scholar (1111319N) and receives funding from B-SMART European Union (EU) Horizon 2020 (grant no. 721058) and Stichting Alzheimer Onderzoek, Belgium (SAO). The B.D.S. laboratory is supported by a European Research Council (ERC) grant (grant no. ERC-834682 337 CELLPHASE_AD), FWO, VIB, SAO, the Queen Elisabeth Medical Foundation, and a Methusalem grant from KU Leuven. B.D.S. is the Bax-Vanluffelen Chair for Alzheimer's Disease and is supported by the Opening the Future campaign of Leuven Universiteit Fonds. Work in the E. Salta lab is supported by Alzheimer Nederland (WE.03-2020-04) and Health-Holland (LSHM20095). Conceptualization, H.W. B.D.S. and E.S.; Methodology, H.W. A.P. G.T. S.S. K.D. A.S. L.Z. D.M. R.M. M.F. A.H. B.D.S. E.S.; Investigation, H.W. A.P. G.T. S.S. K.D. E.D. L.W. M.M. T.B. N.T. R.M. M.F. A.H. E.S.; Writing H.W. E.S. and B.D.S. with input from all authors; Supervision, E.S. and B.D.S.; Funding Acquisition, E.S. and B.D.S. L.Z. and D.M. are employees of Janssen Pharmaceutica. We support inclusive, diverse, and equitable conduct of research. Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = jun,

day = "16",

doi = "10.1016/j.isci.2023.106829",

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TY - JOUR

T1 - microRNA-132 regulates gene expression programs involved in microglial homeostasis

AU - Walgrave, Hannah

AU - Penning, Amber

AU - Tosoni, Giorgia

AU - Snoeck, Sarah

AU - Davie, Kristofer

AU - Davis, Emma

AU - Wolfs, Leen

AU - Sierksma, Annerieke

AU - Mars, Mayte

AU - Bu, Taofeng

AU - Thrupp, Nicola

AU - Zhou, Lujia

AU - Moechars, Diederik

AU - Mancuso, Renzo

AU - Fiers, Mark

AU - Howden, Andrew J. M.

AU - De Strooper, Bart

AU - Salta, Evgenia

N1 - Funding Information: We thank Véronique Hendrickx and Jonas Verwaeren for animal husbandry; and Katrien Horré, Katleen Craessaerts, An Snellinx, Elke Vanden Eynde and Tom Jaspers for technical assistance. In addition, we thank Nicola Fattorelli, Pranav Preman, and Anna Martinez Muriana for scientific discussions and critical feedback. The Thy1-YFP mice were a kind gift from Lieve Moons and Lies De Groef (KU Leuven). Part of the schematics in figures was created with BioRender.com. H.W. is a Fonds voor Wetenschappelijk Onderzoek – Vlaanderen (FWO) scholar (1111319N) and receives funding from B-SMART European Union (EU) Horizon 2020 (grant no. 721058) and Stichting Alzheimer Onderzoek, Belgium (SAO). The B.D.S. laboratory is supported by a European Research Council (ERC) grant (grant no. ERC-834682 337 CELLPHASE_AD), FWO, VIB, SAO, the Queen Elisabeth Medical Foundation, and a Methusalem grant from KU Leuven. B.D.S. is the Bax-Vanluffelen Chair for Alzheimer's Disease and is supported by the Opening the Future campaign of Leuven Universiteit Fonds. Work in the E. Salta lab is supported by Alzheimer Nederland (WE.03-2020-04) and Health-Holland (LSHM20095). Conceptualization, H.W. B.D.S. and E.S.; Methodology, H.W. A.P. G.T. S.S. K.D. A.S. L.Z. D.M. R.M. M.F. A.H. B.D.S. E.S.; Investigation, H.W. A.P. G.T. S.S. K.D. E.D. L.W. M.M. T.B. N.T. R.M. M.F. A.H. E.S.; Writing H.W. E.S. and B.D.S. with input from all authors; Supervision, E.S. and B.D.S.; Funding Acquisition, E.S. and B.D.S. L.Z. and D.M. are employees of Janssen Pharmaceutica. We support inclusive, diverse, and equitable conduct of research. Copyright: © 2023 The Author(s)

PY - 2023/6/16

Y1 - 2023/6/16

N2 - microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.

AB - microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.

KW - Molecular biology

KW - Neuroscience

KW - Omics

UR - http://www.scopus.com/inward/record.url?scp=85159837099&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2023.106829

DO - 10.1016/j.isci.2023.106829

M3 - Article

C2 - 37250784

AN - SCOPUS:85159837099

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 6

M1 - 106829

ER -

microRNA-132 regulates gene expression programs involved in microglial homeostasis

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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