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

iScience. 2023 May 6;26(6):106829. doi: 10.1016/j.isci.2023.106829. eCollection 2023 Jun 16.

Authors

Hannah Walgrave^{1

2}, Amber Penning³, Giorgia Tosoni³, Sarah Snoeck³, Kristofer Davie^{1

4}, Emma Davis⁵, Leen Wolfs^{1

2}, Annerieke Sierksma^{1

2}, Mayte Mars³, Taofeng Bu^{1

2}, Nicola Thrupp^{1

2}, Lujia Zhou⁶, Diederik Moechars⁶, Renzo Mancuso^{7

8}, Mark Fiers^{1

2}, Andrew J M Howden⁹, Bart De Strooper^{1

2

5}, Evgenia Salta³

Affiliations

¹ VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium.
² KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium.
³ Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands.
⁴ VIB-KU Leuven Center for Brain & Disease Research, Bioinformatics Core Facility, 3000 Leuven, Belgium.
⁵ UK Dementia Research Institute at UCL, London WC1E 6BT, UK.
⁶ Discovery Neuroscience, Janssen Research and Development, Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
⁷ Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, VIB, 2610 Antwerp, Belgium.
⁸ Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium.
⁹ UK Dementia Research Institute, University of Dundee, Dundee DD1 4HN, UK.

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.