Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice.

Cara J Westmark,Pamela R Westmark,Brian C Ray,Sara H Abozeid,Kelsey M Stein,Crystal M Hervey,James S Malter,M Shahriar Salamat,Levi A Stodola,Michael Tranfaglia,Elizabeth M Berry-Kravis,Corinna Burger,Kenneth J O'Riordan,Sergio T Ferreira

doi:10.1371/journal.pone.0026549

Cara J Westmark, Pamela R Westmark + Show 12 more

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https://doi.org/10.1371/journal.pone.0026549

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Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid β-protein precursor (AβPP) mRNA. Cleavage of AβPP can produce β-amyloid (Aβ), a 39–43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aβ is over-expressed in the brain of Fmr1KO mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AβPP/Aβ rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS), anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD) in Fmr1KO mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ1–42 was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aβ is sequestered in the brain. Evolving therapies directed at reducing Aβ in AD may be applicable to FXS and Aβ may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.

Highlights

Fragile X syndrome (FXS) is an X chromosome-linked disorder characterized by highly variable intellectual disability, autistic-like behavior and seizures [1]
Reduces audiogenic seizures (AGS) Compared to WT, Fmr1KO mice exhibit AGS [20], altered anxiety [21,22,23] and dendritic spine dysmorphogenesis [24,25,26], features shared with patients with FXS [1,27,28]
In order to establish if amyloid b-protein precursor (AbPP) or Ab directly contributed to FXS pathogenesis, we modulated AbPP and Ab expression in Fmr1KO mice

Summary

Introduction

FXS is an X chromosome-linked disorder characterized by highly variable intellectual disability, autistic-like behavior and seizures [1]. FMRP is a multi-functional mRNA binding protein involved in the dendritic transport, localization and translational regulation of several hundred mRNA ligands [4,5,6,7,8,9]. In the absence of FMRP, dendritic spine morphology and function are abnormal [10]. FXS is likely caused by the inappropriate, post-synaptic expression of one or more FMRP mRNA targets. We have previously demonstrated that postsynaptic translation of App mRNA is regulated by FMRP through a mGluR5-dependent pathway. In the absence of FMRP, excess AbPP and its catabolites Ab1–40 and Ab1–42, accumulate in the brains of middle-aged Fmr1KO mice [11]

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