title: Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease.
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.
authors.affiliation: Institute of Cellular Biology and Neurobiology (IBCN), Consiglio Nazionale delle Ricerche, Via Del Fosso di Fiorano, 64 00143, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Borreca
authors.affiliation: University of Rome, La Sapienza. Piazza Aldo Moro, Rome, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Gironi
authors.affiliation: Institute of Translational Pharmacology (IFT)-National Research Council (CNR), Via Fosso del Cavaliere, 100-00133, Rome, Italy.|European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64-65 00143, Rome, Italy.
authors.forename: Giusy
authors.initials: G
authors.lastname: Amadoro
authors.affiliation: Institute of Cellular Biology and Neurobiology (IBCN), Consiglio Nazionale delle Ricerche, Via Del Fosso di Fiorano, 64 00143, Rome, Italy. martine.teule@cnr.it.|Fondazione Santa Lucia, Via del Fosso di Fiorano, 64 00143, Rome, Italy. martine.teule@cnr.it.
authors.forename: Martine
authors.initials: M
authors.lastname: Ammassari-Teule
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D014020:Tissue Extracts; D014158:Transcription, Genetic
chemical_list: D016564:Amyloid beta-Protein Precursor; D051860:Fragile X Messenger Ribonucleoprotein 1; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D050505:Mutant Proteins; D012333:RNA, Messenger; D014020:Tissue Extracts
keywords: APP; Alzheimer disease; FMRP; RNA binding protein; SAD; Translational control; hnRNP C