The regulation of AβPP expression by RNA-binding proteins

Abstract

Amyloid β-protein precursor (AβPP) is cleaved by β- and γ-secretases to liberate amyloid beta (Aβ), the predominant protein found in the senile plaques associated with Alzheimer’s disease (AD) and Down syndrome (Masters et al., 1985). Intense investigation by the scientific community has centered on understanding the molecular pathways that underlie the production and accumulation of Aβ Therapeutics that reduce the levels of this tenacious, plaque-promoting peptide may reduce the ongoing neural dysfunction and neuronal degeneration that occurs so profoundly in AD. AβPP and Aβ production are highly complex and involve still to be elucidated combinations of transcriptional, post-transcriptional, translational and post-translational events that mediate the production, processing and clearance of these proteins. Research in our laboratory for the past two decades has focused on the role of RNA binding proteins (RBPs) in mediating the post-transcriptional as well as translational regulation of APP messenger RNA (mRNA). This review article summarizes our findings, as well as those from other laboratories, describing the identification of regulatory RBPs, where and under what conditions they interact with APP mRNA and how those interactions control AβPP and Aβ synthesis.

Transient upregulation of translational efficiency in prodromal Tg2576 mice precipitates AD symptoms

“…Regarding Tg2576 hAPP mutants, without excluding the presence of specific translational influences deriving from the hamster prion promoter, there is evidence that once the transgene is inserted in the mouse genome, the regulators of hAPP translation in the symptomatic phase undergo the same alterations as those observed in human patients. For example, consistent with data showing that the two RNA binding proteins, Fragile-X Mental Retardation Protein (FMRP) and heteronuclear Ribonucleoprotein C (hnRNP C), exert an opposite control on APP translation (Lee EK et al, 2010;Westmark CJ et al, 2012), we reported that the enhancement of hAPP levels in hippocampal extracts from both symptomatic Tg2565 mice and sporadic AD patients is accompanied by a downregulation of FMRP and an upregulation of hn RNP C (Borreca et al, 2016). We also noticed in the mutant mice that the stronger increase in hAPP and the maximal dysregulation of FMRP and hnRNP C were observed when mice were 1-and 3-month old, i.e., before or immediately after A oligomers, synaptic failure and cognitive deterioration could be detected.…”

APP Causes Hyperexcitability in Fragile X Mice

“…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).…”

“…FMRP is an RNA binding protein (RBP) that plays a pivotal role in synaptic function. It is one of numerous RBP that interact with amyloid precursor protein ( App ) mRNA to regulate post-transcriptional and/or translational events involved in the synthesis of APP (Westmark and Malter, 2012). Specifically, FMRP binds to a guanine-rich region in the coding region of App mRNA and regulates APP translation through a metabotropic glutamate receptor 5 (mGluR 5 )-dependent pathway (Westmark and Malter, 2007).…”

Unspecific binding of cRNA probe to plaques in two mouse models for Alzheimer’s disease

“…The three-dimensional structure of the plaques, which contain Aβ fibres, degraded neurons and microglia, can possibly result in a similarly high density of cells and/or cellular debris, which might attract RNA probes. Furthermore, it has been found that the expression of APP is regulated by RNA-binding proteins [24]. If these proteins are located in and around the plaques, they might act like adhesion traps for RNA.…”