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

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 ribonuclear 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. Here we show that, as expected, human APP is overexpressed in hippocampal total extract of Tg2576 mice at all age points. APP overexpression, however, is maximal in pre-symptomatic 1-month old mutants and concurrently associates with a reduction of FMRP and an augmentation of hnRNP C expression. 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 RBP targets in the AD brain 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.