The amyloid precursor protein (APP) and its proteolytic product amyloid beta (A) 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 APPandA load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1 (IL-l). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of A, suggesting a possible role for miR-101 in neuropathological conditions
MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons / Vilardo, E; Barbato, C; Ciotti, Mt; Cogoni, Carlo; Ruberti, F.. - In: JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 1083-351X. - STAMPA. - 285(24):(2010), pp. 18344-18351.
MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons.
COGONI, Carlo;
2010
Abstract
The amyloid precursor protein (APP) and its proteolytic product amyloid beta (A) 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 APPandA load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1 (IL-l). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of A, suggesting a possible role for miR-101 in neuropathological conditionsI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.