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

Abstract

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.

Multifarious Functions of the Fragile X Mental Retardation Protein

“…In the mouse FXS model, genetically reducing APP levels prevents hyperexcitability and corrects behavioral, postsynaptic dendritic spine and glutamate signaling defects [14,68]. Dual dysregulation of APP and α-secretase ADAM10 in the mouse FXS model during the critical period activates the MAP kinase pathway to cause synaptogenic and behavioral deficits [72]. …”

APP Causes Hyperexcitability in Fragile X Mice

“…In neurons that overexpress APP, Aβ depresses excitatory synaptic transmission (Kamenetz et al, 2003). In Fmr1 KO mice, Aβ levels are elevated in older mice but reduced in juvenile mice compared to WT controls (Westmark et al, 2011; Pasciuto et al, 2015). Thus, increased α-secretase and/or decreased BACE1 processing during postnatal development could result in decreased Aβ levels and increased synaptic transmission (Jin and Warren, 2000) Altered APP expression could affect scaffolding protein interactions at the postsynaptic density.…”

“…APP does not co-immunoprecipitate with Homer1 (Parisiadou et al, 2008); however, Aβ induces disassembly of Homer1b and Shank1 clusters (Roselli et al, 2009). (Westmark and Malter, 2012) APP or metabolites could alter the activity of intracellular signaling pathways such as ERK and mTOR (Young et al, 2009; Ma et al, 2010; Caccamo et al, 2011; Chasseigneaux et al, 2011; Pasciuto et al, 2015). Both of these pathways play pivotal roles in FXS pathology (Osterweil et al, 2010; Hoeffer et al, 2012).…”

“…We have observed that both over- and under-expression of APP increases seizure propensity in juvenile Fmr1 KO mice suggesting that tight regulation of this protein may be necessary to mitigate hyperexcitability in FXS (Westmark et al, 2010, 2011). Genetic reduction of APP in Fmr1 KO mice rescues plasticity (mGluR-LTD, neocortical hyperexcitability, epileptiform discharge duration but not induction), dendritic spines (percent mature spines but not dendritic spine length), protein synthesis, behavior (open field, marble burying), and AGS (Westmark et al, 2011; Pasciuto et al, 2015). The partial rescue of dendritic spines and epileptiform discharges in the Fmr1 KO /APP HET suggests that APP is necessary but not sufficient to maintain synaptic homeostasis.…”

“…In support of this hypothesis, genetic knockout of one App allele in Fmr1 KO mice ( Fmr1 KO / APP HET mice) reduces APP expression in the Fmr1 KO to wild type (WT) levels and rescues audiogenic-induced seizures (AGS), the percentage of mature spines, open field and marble burying behavioral phenotypes, and mGluR-LTD (Westmark et al, 2011). APP and metabolite levels are altered in Fmr1 KO mice and FXS patients (Sokol et al, 2006; Westmark et al, 2011; Erickson et al, 2014; Pasciuto et al, 2015; Ray et al, 2016). Thus, APP is a potential therapeutic target as well as blood-based biomarker for FXS (Berry-Kravis et al, 2013; Westmark et al, 2016), and it is of interest to determine the effect(s) of APP levels on additional disease phenotypes.…”