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Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer's disease

Research output: Contribution to journalArticlepeer-review

Hannah Walgrave, Sriram Balusu, Sarah Snoeck, Elke Vanden Eynden, Katleen Craessaerts, Nicky Thrupp, Leen Wolfs, Katrien Horré, Yannick Fourne, Alicja Ronisz, Edina Silajdžić, Amber Penning, Giorgia Tosoni, Zsuzsanna Callaerts-Vegh, Rudi D'Hooge, Dietmar Rudolf Thal, Henrik Zetterberg, Sandrine Thuret, Mark Fiers, Carlo Sala Frigerio & 2 more Bart De Strooper, Evgenia Salta

Original languageEnglish
Pages (from-to)1805-1821.e8
JournalCell Stem Cell
Volume28
Issue number10
DOIs
Published7 Oct 2021

Bibliographical note

Funding Information: We thank Véronique Hendrickx and Jonas Verwaeren for animal husbandry; Sebastian Munck, Nikky Corthout, Axelle Kerstens (LiMoNe, VIB), the VIB Nucleomics Core of Leuven, the VIB-KU Leuven FACS Core, An Snellinx, Isabel Salas, Dries T’Syen, Sara Calafate, Jeroen Vanderlinden, Natalia Gunko, Dorien Vandael, Annette Gärtner, and Jenny Peeters for providing technical assistance and resources; and Annerieke Sierksma, Patrik Verstreken, Laure Bally-Cuif, Joris De Wit, Pierre Vanderhaeghen, and Matthew Holt for critical discussions and feedback. The APP/PS1 mice were a kind gift from Mathias Jucker (DZNE, Germany), the App NL-G-F mice were kindly provided by Takaomi Saido (RIKEN Brain Science Institute, Japan), and the Nestin:GFP mice were from Grigori Enikolopov (Stony Brook University, New York). The PGK lentiviral vector was a kind gift from Antonella Consiglio. Part of the graphical abstract was created with BioRender.com. H.W. is a Fonds voor Wetenschappelijk Onderzoek – Vlaanderen (FWO) Scholar and receives funding from B-SMART European Union (EU) Horizon 2020 and Stichting Alzheimer Onderzoek, Belgium (SAO). D.R.T. is funded by grants from FWO ( G0F8516N Odysseus) and VIND ( IWT 135043 ). Work in the S.T. lab is supported by U.K. Medical Research Council grants MR/N030087/1 and MR/S00484X/1 . H.Z. is a Wallenberg Scholar. Work in the B.D.S. laboratory is supported by a European Research Council (ERC) grant ERC-2010-AG_268675 , FWO , KU Leuven , VIB , Stichting Alzheimer Onderzoek, Belgium (SAO), the Elisabeth Foundation , VIND ( IWT 135043 ), and a Methusalem grant from KU Leuven and the Flemish Government . B.D.S. is the Bax-Vanluffelen Chair for Alzheimer’s Disease and is supported directly by the Opening the Future campaign of Leuven Universiteit Fonds . E. Salta has previously received funding from FWO , the Alzheimer's Association (AA), and Stichting Alzheimer Onderzoek, Belgium (SAO). Work in the E. Salta lab is currently supported by Alzheimer Nederland , Health-Holland , and the AA . Funding Information: We thank V?ronique Hendrickx and Jonas Verwaeren for animal husbandry; Sebastian Munck, Nikky Corthout, Axelle Kerstens (LiMoNe, VIB), the VIB Nucleomics Core of Leuven, the VIB-KU Leuven FACS Core, An Snellinx, Isabel Salas, Dries T'Syen, Sara Calafate, Jeroen Vanderlinden, Natalia Gunko, Dorien Vandael, Annette G?rtner, and Jenny Peeters for providing technical assistance and resources; and Annerieke Sierksma, Patrik Verstreken, Laure Bally-Cuif, Joris De Wit, Pierre Vanderhaeghen, and Matthew Holt for critical discussions and feedback. The APP/PS1 mice were a kind gift from Mathias Jucker (DZNE, Germany), the AppNL-G-F mice were kindly provided by Takaomi Saido (RIKEN Brain Science Institute, Japan), and the Nestin:GFP mice were from Grigori Enikolopov (Stony Brook University, New York). The PGK lentiviral vector was a kind gift from Antonella Consiglio. Part of the graphical abstract was created with BioRender.com. H.W. is a Fonds voor Wetenschappelijk Onderzoek ? Vlaanderen (FWO) Scholar and receives funding from B-SMART European Union (EU) Horizon 2020 and Stichting Alzheimer Onderzoek, Belgium (SAO). D.R.T. is funded by grants from FWO (G0F8516N Odysseus) and VIND (IWT 135043). Work in the S.T. lab is supported by U.K. Medical Research Council grants MR/N030087/1 and MR/S00484X/1. H.Z. is a Wallenberg Scholar. Work in the B.D.S. laboratory is supported by a European Research Council (ERC) grant ERC-2010-AG_268675, FWO, KU Leuven, VIB, Stichting Alzheimer Onderzoek, Belgium (SAO), the Elisabeth Foundation, VIND (IWT 135043), and a Methusalem grant from KU Leuven and the Flemish Government. B.D.S. is the Bax-Vanluffelen Chair for Alzheimer's Disease and is supported directly by the Opening the Future campaign of Leuven Universiteit Fonds. E. Salta has previously received funding from FWO, the Alzheimer's Association (AA), and Stichting Alzheimer Onderzoek, Belgium (SAO). Work in the E. Salta lab is currently supported by Alzheimer Nederland, Health-Holland, and the AA. Conceptualization, H.W. B.D.S. and E. Salta; Methodology, H.W. S.B. K.C. L.W. Z.C.-V. R.D.H. D.R.T. E. Silajd?i?, S.T. C.S.F. B.D.S. and E. Salta; Investigation, H.W. S.B. S.S. E.V.E. K.C. K.H. L.W. A.R. E. Silajd?i?, A.P. G.T. C.S.F. and E. Salta; Software, M.F. N.T. and Y.F.; Formal Analysis, M.F. N.T. Y.F. and E. Salta; Resources, Z.C.-V. R.D.H. D.R.T. H.Z. and S.T.; Writing ? Review & Editing, E. Salta and B.D.S. with input from all authors; Supervision, E. Salta and B.D.S.; Funding Acquisition, E. Salta and B.D.S. The authors declare no competing interests. Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer's disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.

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