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
Affiliations
Hannah Walgrave
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium
Amber Penning
Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands
Giorgia Tosoni
Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands
Sarah Snoeck
Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands
Kristofer Davie
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; VIB-KU Leuven Center for Brain & Disease Research, Bioinformatics Core Facility, 3000 Leuven, Belgium
Emma Davis
UK Dementia Research Institute at UCL, London WC1E 6BT, UK
Leen Wolfs
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium
Annerieke Sierksma
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium
Mayte Mars
Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands
Taofeng Bu
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium
Nicola Thrupp
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium
Lujia Zhou
Discovery Neuroscience, Janssen Research and Development, Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium
Diederik Moechars
Discovery Neuroscience, Janssen Research and Development, Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium
Renzo Mancuso
Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, VIB, 2610 Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium
Mark Fiers
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium
Andrew J.M. Howden
UK Dementia Research Institute, University of Dundee, Dundee DD1 4HN, UK
Bart De Strooper
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; KU Leuven, Department of Neurosciences, Leuven Brain Institute (LBI), 3000 Leuven, Belgium; UK Dementia Research Institute at UCL, London WC1E 6BT, UK; Corresponding author
Evgenia Salta
Netherlands Institute for Neuroscience, 1105 BA Amsterdam, the Netherlands; Corresponding author
Summary: 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.
