Journal
NEURON
Volume 87, Issue 2, Pages 382-398Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2015.06.032
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Funding
- Stichting Alzheimer Onderzoek - Fondation Recherche Maladie Alzheimer (SAO-FMA)
- Vlaams Instituut voor Biotechnologie (VIB)
- KU Leuven (Opening the Future)
- European Research Projects on Neurodevelopmental Disorders NEURON ERA-NET
- Associazione Italiana Sindrome X Fragile
- Compagnia San Paolo
- Fondation Jerome Lejeune
- European Research Council [ERC-2010-AG_268675]
- KU Leuven/Flemish Government
- Bax-Vanluffelen Chair for Alzheimer's Disease
- Opening the Future of the Leuven Universiteit Fonds (LUF)
- Fonds Wetenschappelijke Onderzoek (FWO)
- KU Leuven Geconcerteerde Onderzoeksactie (GOA) [12/008]
- Deutsche Forschungsgemeinschaft (DFG) [MU 1457/8-1, 1457/9-1]
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The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The beta-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the alpha-secretase ADAM10 leads to the production of an excess of soluble APP alpha (sAPP alpha). In FXS, sAPP alpha signals through the metabotropic receptor that, activating theMAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPa levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.
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