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Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease

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Abstract

Amyloid precursor protein (APP) is overexpressed in familiar and sporadic Alzheimer Disease (AD) patients suggesting that, in addition to abnormalities in APP cleavage, enhanced levels of APP full length might contribute to the pathology. Based on data showing that the two RNA binding proteins (RBPs), Fragile-X Mental Retardation Protein (FMRP) and heteronuclear Ribonucleoprotein C (hnRNP C), exert an opposite control on APP translation, we have analyzed whether expression and translation of these two RBPs vary in relation to changes in APP protein and mRNA levels in the AD brain at 1, 3, and 6 months of age. Here, we show that, as expected, human APP is overexpressed in hippocampal total extract from Tg2576 mice at all age points. APP overexpression, however, is not stable over time but reaches its maximal level in 1-month-old mutants in association with the stronger (i) reduction of FMRP and (ii) augmentation of hnRNP C. APP levels then decrease progressively as a function of age in close relationship with the gradual normalization of FMRP and hnRNP C levels. Consistent with the mouse data, expression of FMRP and hnRNP C are, respectively, decreased and increased in hippocampal synaptosomes from sporadic AD patients. Our findings identify two RBP targets that might be manipulated for reducing abnormally elevated levels of APP in the AD brain, with the hypothesis that acting upstream of amyloidogenic processing might contribute to attenuate the amyloid burden.

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Funding

This research was funded by MIUR/CNR on the project for aging with the project: “Disease mechanism of working memory load capacity in aging and Alzheimer disease” to M.A.T (coordinator of the project) and A.B... The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Institute of Cellular Biology and Neurobiology (IBCN), Consiglio Nazionale delle Ricerche, Via Del Fosso di Fiorano, 64 00143, Rome, Italy

    Antonella Borreca & Martine Ammassari-Teule

  2. University of Rome, La Sapienza. Piazza Aldo Moro, Rome, Italy

    Katia Gironi

  3. Institute of Translational Pharmacology (IFT)-National Research Council (CNR), Via Fosso del Cavaliere, 100-00133, Rome, Italy

    Giusy Amadoro

  4. European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64-65 00143, Rome, Italy

    Giusy Amadoro

  5. Fondazione Santa Lucia, Via del Fosso di Fiorano, 64 00143, Rome, Italy

    Martine Ammassari-Teule

Authors
  1. Antonella Borreca
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  2. Katia Gironi
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  4. Martine Ammassari-Teule
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Corresponding author

Correspondence to Martine Ammassari-Teule.

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Supplementary Fig. 1

Analysis of PS1 levels expression in the hippocampus of Tg2576 mice during development and adulthood. Upper panel: histograms showing the levels of PS1 in Tg2576 and WT hippocampi. Lower panel: representative immunoblots used for quantification. Data were normalized with β-actin and expressed as mean ± s.e.m (TIFF 3804 kb)

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Borreca, A., Gironi, K., Amadoro, G. et al. Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease. Mol Neurobiol 53, 3227–3234 (2016). https://doi.org/10.1007/s12035-015-9229-8

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  • DOI: https://doi.org/10.1007/s12035-015-9229-8

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