Elsevier

Ageing Research Reviews

Volume 11, Issue 4, September 2012, Pages 450-459
Ageing Research Reviews

Review
The regulation of AβPP expression by RNA-binding proteins

https://doi.org/10.1016/j.arr.2012.03.005Get rights and content

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.

Highlights

► Multiple RBPs interact with distinct cis-elements in APP mRNA. ► hnRNP C and nucleolin bind to 3′-UTR cis-elements and mediate message stability. ► IRP1 binds to an IRE in the 5′-UTR of APP mRNA to regulate translation. ► FMRP and hnRNP C compete for binding to a CR G-rich element to modulate translation. ► APP mRNA is subject to diverse post-transcriptional regulatory processes.

Introduction

The APP gene is located on human chromosome 21 and codes for AβPP, a ubiquitously expressed, transmembrane protein that localizes to post-synaptic densities, axons, dendrites and neuromuscular junctions (NMJ) (Akaaboune et al., 2000, Shigematsu et al., 1992), consistent with its multiple roles in cell adhesion (Soba et al., 2005), synapse formation (Torroja et al., 1999, Yang et al., 2005) and synapse maturation (Akaaboune et al., 2000). Differential processing of AβPP by non-amyloidogenic (α- and γ-) or amyloidogenic (β- and γ-) secretases produces soluble AβPP (sAβPPα and sAβPPβ), truncated or full-length amyloid-beta (Aβ) and variable length carboxy-terminal fragments (CTFs). The over-production and ultimate aggregation of Aβ is associated with AD and Down syndrome pathology with current evidence suggesting a more pathogenic role for soluble, pre-aggregated Aβ. Despite decades of investigation, much remains to be learned about the normal physiological function of Aβ and other AβPP catabolites as well as the cellular and molecular pathways that regulate their generation. Clearly, a better understanding of AβPP biology and gene expression will provide new avenues for therapeutic intervention in a number of highly prevalent and currently untreatable neurological disorders.

Our laboratory has studied the mechanisms that underlie the stability and translation of APP mRNA. These studies were triggered by the realization that the 3′ untranslated regions (3′ UTR) of mouse, rat, human and other species of APP mRNA contained islands of substantial homology, consistent with the presence of cis-acting elements. We hypothesized that APP mRNA was subject to activation-dependent changes in stability and/or translation. Such events could account for both increased mRNA under steady state levels as well as increased translation. Indeed, we and other groups have successfully defined multiple cis-regulatory elements within the 5′-UTR, coding region (CR) and 3′-UTR of APP mRNA that mediate the post-transcriptional stability and/or translation of APP mRNA (Zaidi and Malter, 1994, Amara et al., 1999, Rogers et al., 2002, Westmark et al., 2006, Westmark and Malter, 2007) as well as identified a number of RBPs that bind to these cis-elements (Zaidi et al., 1994, Zaidi and Malter, 1995, Westmark and Malter, 2007, Broytman et al., 2008, Lee et al., 2010, Cho et al., 2010). These mRNA/RBP complexes control the degradation, stability and/or translation of APP mRNA, which directly determines how much AβPP is synthesized and thus available for processing toward or away from amyloidogenic endpoints.

This review article summarizes our findings, as well as those from the Rogers, Amara and Gorospe laboratories, describing the mRNA/RBP complexes and signaling pathways that regulate AβPP expression. A detailed understanding of the molecular interactions that regulate AβPP synthesis may provide novel avenues for therapeutic intervention in the treatment of AD and other Aβ-related disorders.

Section snippets

cis-Regulatory elements in APP mRNA

mRNA stability is an important control point in gene expression. The mRNAs of certain classes of regulatory proteins, such as oncogenes, cytokines, lymphokines and transcriptional activators are extremely labile (Brewer, 1991, Shaw and Kamen, 1986). Many of these mRNAs contain a common AUUUA pentamer in their 3′-UTR, which confers message instability through interactions with RBPs, such as AU-rich binding factor (AUBF) (Malter, 1989, Gillis and Malter, 1991), AUF1 (Wang et al., 1998) or TTP (

RNA binding proteins that interact with APP mRNA

Given the numerous cis-elements described above, it is hardly surprising that multiple RBPs have been identified that interact with APP mRNA. Many of these proteins are known to bind to multiple mRNAs and have diverse functions including nuclear/cytoplasmic shuttling, RNA helicase activity, iron homeostasis and translational repression. Interestingly, with the exception of the 5′-UTR IRE-like domain, the cis-elements in APP mRNA do not show obvious or substantial homology to other mRNAs. As it

Post-transcriptional gene regulation of APP mRNA

Post-transcriptional gene regulation is a complex process involving interaction of cis-regulatory elements in the 3′-UTR of mRNAs with trans factors or RBPs. These interactions are regulated by cell signaling events and likely result in alterations in higher order structures of the mRNAs. A summary of the identified cis-regulatory elements and trans factors involved in the pos-transcriptional gene regulation of APP mRNA is depicted in Fig. 1. The role of microRNAs (miRNAs) is also evolving as

Translational regulation of APP mRNA

App mRNAs are highly associated with polyribosomes in rat brain (Denman et al., 1991) suggesting that translational regulation could play an important role in AβPP production. At least two identified cis-elements regulate translation of APP mRNA including an IRE in the 5′-UTR (Rogers et al., 2002) and a guanine-rich element in the CR (Westmark and Malter, 2007, Lee et al., 2010). RBPs, which modulate ribosomal access and initiation, often mediate translational control at the synapse. Two of the

The need for new therapeutic approaches

The ultimate reason to understand the cellular and molecular pathways underlying AβPP and Aβ production is to facilitate the rationale development of reliable and safe therapeutics. All of the currently approved drugs for the treatment of AD act on healthy neurons to (1) compensate for reduced acetylcholine in the case of cholinesterase inhibitors, or (2) modulate NMDA receptor activity in the case of memantine. They improve cognitive ability for a year or less, but do not reduce amyloid plaque

Acknowledgments

This work was supported by the National Institutes of Health grants R01-AG10675, RO1-DA026067, P30-HD03352, T32-AG00213, the Alzheimer's Drug Discovery Foundation, FRAXA Research Foundation and the Wisconsin Comprehensive Memory Program. The sponsors had no role in the writing of this review article or the decision to publish. The authors thank Dr. Pamela Westmark for critical reading of the manuscript.

References (121)

  • H.H. Cho et al.

    Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1

    Journal of Biological Chemistry

    (2010)
  • J.C. Darnell et al.

    Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function

    Cell

    (2001)
  • R. Denman et al.

    Distribution and activity of alternatively spliced Alzheimer amyloid peptide precursor and scrapie PrP mRNAs on rat brain polysomes

    Archives of Biochemistry and Biophysics

    (1991)
  • N. Dolzhanskaya et al.

    The fragile X mental retardation protein interacts with U-rich RNAs in a yeast three-hybrid system

    Biochemical and Biophysical Research Communications

    (2003)
  • E. Egyhazi et al.

    Effects of anti-C23 (nucleolin) antibody on transcription of ribosomal DNA in chironomus salivary gland cells

    Experimental Cell Research

    (1988)
  • M. Fahling et al.

    Role of nucleolin in posttranscriptional control of MMP-9 expression

    Biochimica et Biophysica Acta

    (2005)
  • P. Gillis et al.

    The adenosine-uridine binding factor recognizes the AU-rich elements of cytokine, lymphokine, and oncogene mRNAs

    Journal of Biological Chemistry

    (1991)
  • B.J. Hamilton et al.

    Association of heterogeneous nuclear ribonucleoprotein A1 and C proteins with reiterated AUUUA sequences

    Journal of Biological Chemistry

    (1993)
  • J.H. Heaton et al.

    Identification and cDNA cloning of a novel RNA-binding protein that interacts with the cyclic nucleotide-responsive sequence in the type-1 plasminogen activator inhibitor mRNA

    Journal of Biological Chemistry

    (2001)
  • N. Inamura et al.

    Cellular and subcellular distributions of translation initiation, elongation and release factors in rat hippocampus

    Brain Research Molecular Brain Research

    (2003)
  • H.Y. Kim et al.

    Translational repressor activity is equivalent and is quantitatively predicted by in vitro RNA binding for two iron-responsive element-binding proteins, IRP1 and IRP2

    Journal of Biological Chemistry

    (1995)
  • J.M. Long et al.

    MicroRNA-101 downregulates Alzheimer's amyloid-beta precursor protein levels in human cell cultures and is differentially expressed

    Biochemical and Biophysical Research Communications

    (2011)
  • N. Minshall et al.

    CPEB interacts with an ovary-specific eIF4E and 4E-T in early Xenopus oocytes

    Journal of Biological Chemistry

    (2007)
  • K.Y. Miyashiro et al.

    RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice

    Neuron

    (2003)
  • R. Parker et al.

    P bodies and the control of mRNA translation and degradation

    Molecular Cell

    (2007)
  • E.M. Rockenstein et al.

    Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer's disease

    Journal of Biological Chemistry

    (1995)
  • J.T. Rogers et al.

    An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript

    Journal of Biological Chemistry

    (2002)
  • J.T. Rogers et al.

    Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5′-untranslated region sequences

    Journal of Biological Chemistry

    (1999)
  • T.K. Sengupta et al.

    Identification of nucleolin as an AU-rich element binding protein involved in bcl-2 mRNA stabilization

    Journal of Biological Chemistry

    (2004)
  • G. Shaw et al.

    A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation

    Cell

    (1986)
  • K. Shigematsu et al.

    Localization of amyloid precursor protein in selective postsynaptic densities of rat cortical neurons

    Brain Research

    (1992)
  • Y. Akao et al.

    The rck/p54 candidate proto-oncogene product is a 54-kilodalton D-E-A-D box protein differentially expressed in human and mouse tissues

    Cancer Research

    (1995)
  • S.A. Ansari et al.

    Interaction of YB1 with human immunodeficiency virus type 1 tat and TAR RNA modulates viral promoter activity

    Journal of General Virology

    (1999)
  • C. Bagni et al.

    From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome

    Nature Reviews Neuroscience

    (2005)
  • S. Bandyopadhyay et al.

    Novel drug targets based on metallobiology of Alzheimer's disease

    Expert Opinion on Therapeutic Targets

    (2010)
  • F. Bard et al.

    Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease

    Nature Medicine

    (2000)
  • P. Belenguer et al.

    Protein kinase NII and the regulation of rDNA transcription in mammalian cells

    Nucleic Acids Research

    (1989)
  • P. Bouvet et al.

    Sequence-specific RNA recognition by the Xenopus Y-box proteins. An essential role for the cold shock domain

    Journal of Biological Chemistry

    (1995)
  • G. Brewer

    An A + U-rich element RNA-binding factor regulates c-myc mRNA stability in vitro

    Molecular and Cellular Biology

    (1991)
  • O. Broytman et al.

    Rck/p54 interacts with APP mRNA as part of a multi-protein complex and enhances APP mRNA and protein expression in neuronal cell lines

    Neurobiology of Aging

    (2008)
  • O. Broytman et al.

    Anti-abeta: the good, the bad, and the unforeseen

    Journal of Neuroscience Research

    (2004)
  • E.E. Capowski et al.

    Y box-binding factor promotes eosinophil survival by stabilizing granulocyte-macrophage colony-stimulating factor mRNA

    Journal of Immunology

    (2001)
  • D. Caput et al.

    Identification of a common nucleotide sequence in the 3′-untranslated region of mRNA molecules specifying inflammatory mediators

    Proceedings of the National Academy of Sciences of the United States of America

    (1986)
  • S. Ceman et al.

    Isolation of an FMRP-associated messenger ribonucleoprotein particle and identification of nucleolin and the fragile X-related proteins as components of the complex

    Molecular and Cellular Biology

    (1999)
  • E. Check

    Nerve inflammation halts trial for Alzheimer's drug

    Nature

    (2002)
  • C.Y. Chen et al.

    Nucleolin and YB1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation

    Genes & Development

    (2000)
  • Y.D. Choi et al.

    Heterogeneous nuclear ribonucleoproteins: role in RNA splicing

    Science

    (1986)
  • Y.D. Choi et al.

    Isolation of the heterogeneous nuclear RNA-ribonucleoprotein complex (hnRNP): a unique supramolecular assembly

    Proceedings of the National Academy of Sciences of the United States of America

    (1984)
  • C.Y. Chu et al.

    Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54

    PLoS Biology

    (2006)
  • S.L. Clarke et al.

    Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe–S cluster

    EMBO Journal

    (2006)
  • Cited by (18)

    View all citing articles on Scopus
    1

    Tel.: +1 214 648 4020.

    View full text