Developing BACE-1 inhibitors for FXS

Abstract

Fragile X syndrome (FXS) is a debilitating genetic disorder with no cure and few therapeutic options. Excessive signaling through metabotropic glutamate receptor 5 in FXS leads to increased translation of numerous synaptic proteins and exaggerated long-term depression. Two of the overexpressed proteins are amyloid-beta protein precursor (APP) and its metabolite amyloid-beta, which have been well-studied in Alzheimer's disease (AD). Here we discus the possibility that pharmaceuticals under study for the modulation of these proteins in AD might be viable therapeutic strategies for FXS. Specifically, a recently identified acetyltransferase inhibitor that reduces the levels and activity of β-site APP cleaving enzyme (BACE-1) has strong potential to attenuate BACE-1 activity and maintain homeostatic levels APP catabolites in FXS.

Fragile X and APP: a Decade in Review, a Vision for the Future

“…The dysregulated expression of APP and metabolites in multiple FXS models elicits the hypothesis that drugs under development for AD could be repurposed for FXS [116]. In support of that hypothesis, inhibition of beta-secretase 1 (aka beta-site APP cleaving enzyme 1; BACE1) reduces AGS in juvenile Fmr1 KO mice and rescues altered morphology of shFmr1 mouse neural progenitor cells [36,113].…”

APP Causes Hyperexcitability in Fragile X Mice

“…APP and metabolites play key roles in regulating synaptic activity with both Aβ and sAPPα implicated in positive feedback loops that facilitate mGluR 5 signaling (Casley et al, 2009; Renner et al, 2010; Ferreira and Klein, 2011; Westmark et al, 2011, 2013b; Pasciuto et al, 2015). Thus, the APP rheostat may provide a graded response to mGluR 5 activation through feedback loops involving amyloidogenic and non-amyloidogenic secretase processing.…”

“…Drugs under study for FXS such as acamprosate, AFQ056, donepezil, ganaxolone, lithium, lovastatin, memantine, minocycline and sertraline exhibit on- and/or off-site effects that are expected to modulate APP, Aβ, BACE1, and/or ADAM10 (Westmark et al, 2013b). Targeting APP and metabolites in FXS may allow fine tuning of excitability levels as part of a multi-drug therapeutic approach.…”

“…Targeting APP and metabolites in FXS may allow fine tuning of excitability levels as part of a multi-drug therapeutic approach. Both amyloidogenic and non-amyloidogenic therapies have been proposed to treat FXS (Westmark et al, 2013b; Pasciuto et al, 2015). Both amyloidogenic (Aβ 1−42 ) and non-amyloidogenic (sAPPα) metabolites of APP stimulate phosphorylation of ERK and modulate synthesis of multiple synaptic proteins predicted to be regulated through mGluR 5 /FMRP and to contribute to altered synaptic plasticity (Westmark et al, 2011; Pasciuto et al, 2015).…”

Commentary: Depletion of the Fragile X Mental Retardation Protein in Embryonic Stem Cells Alters the Kinetics of Neurogenesis

“…Of relevance herein, two overexpressed proteins are APP and amyloid-beta (Westmark and Malter, 2007 ), which have been well-studied in Alzheimer's disease (AD). Accumulating evidence suggests that dysregulated levels of APP metabolites contribute to FXS pathology (Figure 1 ), supporting the hypothesis that pharmaceuticals under study for modulation of APP and amyloid-beta in AD may be viable therapeutic strategies for FXS (Westmark et al, 2013 ; Pasciuto et al, 2015 ).…”