Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual...

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Published in:Neuron (Cambridge, Mass.) Vol. 87; no. 2; p. 382
Main Authors: Pasciuto, Emanuela, Ahmed, Tariq, Wahle, Tina, Gardoni, Fabrizio, D'Andrea, Laura, Pacini, Laura, Jacquemont, Sébastien, Tassone, Flora, Balschun, Detlef, Dotti, Carlos G, Callaerts-Vegh, Zsuzsanna, D'Hooge, Rudi, Müller, Ulrike C, Di Luca, Monica, De Strooper, Bart, Bagni, Claudia
Format: Journal Article
Language:English
Published: United States 15.07.2015
Subjects:
ADAM Proteins - genetics
ADAM Proteins - metabolism
ADAM10 Protein
Adolescent
Adult
Age Factors
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases - genetics
Amyloid Precursor Protein Secretases - metabolism
Animals
Animals, Newborn
Cells, Cultured
Cerebral Cortex - cytology
Child
Female
Fragile X Syndrome - genetics
Fragile X Syndrome - pathology
Gene Expression Regulation - genetics
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Humans
Male
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons - drug effects
Neurons - metabolism
Neurons - ultrastructure
Synapses - pathology
Time Factors
Young Adult
ISSN:1097-4199, 1097-4199
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Summary:The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-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 α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα 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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ISSN:1097-4199
1097-4199
DOI:10.1016/j.neuron.2015.06.032