| First Author | Pasciuto E | Year | 2015 |
| Journal | Neuron | Volume | 87 |
| Issue | 2 | Pages | 382-98 |
| PubMed ID | 26182420 | Mgi Jnum | J:227681 |
| Mgi Id | MGI:5702394 | Doi | 10.1016/j.neuron.2015.06.032 |
| Citation | Pasciuto E, et al. (2015) Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome. Neuron 87(2):382-98 |
| abstractText | 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 APPalpha (sAPPalpha). In FXS, sAPPalpha signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPalpha 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. |
