摘要
Synaptic dysfunction and abnormal processing of amyloid precursor protein(APP) are early pathological features in Alzheimer’s disease(AD). Recently, noncoding RNAs such as micro RNAs(mi RNAs) and circular RNAs(circ RNAs) have been reported to contribute to the pathogenesis of AD. We found an age-dependent elevation of mi R-138 in APP/PS1(presenilin-1) mice. Mi R-138 inhibited the expression of ADAM10 [a disintegrin and metalloproteinase domain-containing protein 10], promoted amyloid beta(Ab) production, and induced synaptic and learning/memory deficits in APP/PS1 mice, while its suppression alleviated the AD-like phenotype in these mice. Overexpression of sirtuin 1(Sirt1), a target of mi R-138, ameliorated the mi R-138-induced inhibition of ADAM10 and elevation of Ab in vitro. The circ RNA HDAC9(circ HDAC9) was predicted to contain a mi R-138 binding site in several databases. Its expression was inversely correlated with mi R-138 in both Ab-oligomertreated N2 a cells and APP/PS1 mice, and it co-localized with mi R-138 in the cytoplasm of N2 a cells. Circ HDAC9 acted as a mi R-138 sponge, decreasing mi R-138 expression, and reversing the Sirt1 suppression and excessive Ab production induced by mi R-138 in vitro. Moreover,circ HDAC9 was decreased in the serum of both AD patients and individuals with mild cognitive impairment.These results suggest that the circ HDAC9/mi R-138/Sirt1 pathway mediates synaptic function and APP processing in AD, providing a potential therapeutic target for its treatment.
Synaptic dysfunction and abnormal processing of amyloid precursor protein(APP) are early pathological features in Alzheimer’s disease(AD). Recently, noncoding RNAs such as micro RNAs(mi RNAs) and circular RNAs(circ RNAs) have been reported to contribute to the pathogenesis of AD. We found an age-dependent elevation of mi R-138 in APP/PS1(presenilin-1) mice. Mi R-138 inhibited the expression of ADAM10 [a disintegrin and metalloproteinase domain-containing protein 10], promoted amyloid beta(Ab) production, and induced synaptic and learning/memory deficits in APP/PS1 mice, while its suppression alleviated the AD-like phenotype in these mice. Overexpression of sirtuin 1(Sirt1), a target of mi R-138, ameliorated the mi R-138-induced inhibition of ADAM10 and elevation of Ab in vitro. The circ RNA HDAC9(circ HDAC9) was predicted to contain a mi R-138 binding site in several databases. Its expression was inversely correlated with mi R-138 in both Ab-oligomertreated N2 a cells and APP/PS1 mice, and it co-localized with mi R-138 in the cytoplasm of N2 a cells. Circ HDAC9 acted as a mi R-138 sponge, decreasing mi R-138 expression, and reversing the Sirt1 suppression and excessive Ab production induced by mi R-138 in vitro. Moreover,circ HDAC9 was decreased in the serum of both AD patients and individuals with mild cognitive impairment.These results suggest that the circ HDAC9/mi R-138/Sirt1 pathway mediates synaptic function and APP processing in AD, providing a potential therapeutic target for its treatment.
基金
supported by the National Natural Science Foundation of China (81500925)
