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Ruberti F.,CNR Institute of Neurobiology and Molecular Medicine | Barbato C.,CNR Institute of Neurobiology and Molecular Medicine | Barbato C.,EBRI European Brain Research Institute Fondazione EBRI Rita Levi Montalcini | Cogoni C.,EBRI European Brain Research Institute Fondazione EBRI Rita Levi Montalcini | Cogoni C.,University of Rome La Sapienza
Communicative and Integrative Biology | Year: 2010

Amyloid Precursor Protein (APP) and its proteolytic product amyloid beta (Aβ) are critical in the pathogenesis of Alzheimer's Disease (AD). APP gene duplication and transcriptional upregulation are linked to AD. In addition, normal levels of APP appear to be required for some physiological functions in the developing brain. Several studies in mammalian cell lines and primary neuron cultures indicate that RNA binding proteins and microRNAs interacting with regulatory regions of the APP mRNA modulate expression of APP post-transcriptionally. However, when the various mechanisms of APP posttranscriptional regulation are recruited and which of them are acting in a synergistic fashion to balance APP protein levels, is unclear. Recent studies suggest that further investigation of the molecules and pathways involved in APP post-transcriptional regulation are warranted. © 2010 Landes Bioscience. Source


Vilardo E.,CNR Institute of Neurobiology and Molecular Medicine | Barbato C.,CNR Institute of Neurobiology and Molecular Medicine | Barbato C.,EBRI European Brain Research Institute Fondazione EBRI Rita Levi Montalcini | Ciotti M.,CNR Institute of Neurobiology and Molecular Medicine | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

The amyloid precursor protein (APP) and its proteolytic product amyloid beta (Aβ) are associated with both familial and sporadic forms of Alzheimer disease (AD). Aberrant expression and function of microRNAs has been observed in AD. Here, we show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. Using site-directed mutagenesis, a microRNA responsive element (RE) for miR-101 was identified in the 3′-untranslated region (UTR) of APP. The inhibition of endogenous miR-101 increased APP levels, whereas lentiviral-mediated miR-101 overexpression significantly reduced APP and Aβ load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1β (IL-1β). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of Aβ, suggesting a possible role for miR-101 in neuropathological conditions. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source

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