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

摘要: Summary The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the syndrome (FXS). β-amyloid precursor (APP) is involved in Alzheimer's disease, plays a role synapse formation, upregulated intellectual disabilities. Here, we show that during mouse synaptogenesis human FXS fibroblasts, dual dysregulation of APP α-secretase ADAM10 production an excess soluble APPα (sAPPα). In FXS, sAPPα signals through metabotropic receptor that, activating MAP kinase pathway, synaptic behavioral deficits. Modulation activity reduces levels, restoring translational control, morphology, plasticity. Thus, proper control ADAM10-mediated processing specific developmental postnatal stage crucial for healthy spine formation function(s). Downregulation at synapses may be effective strategy ameliorating phenotypes.