Circular HDAC9/microRNA-138/Sirtuin-1 Pathway Mediates Synaptic and Amyloid Precursor Protein Processing Deficits in Alzheimer's Disease

【Author】

Yanjun Lu;Lu Tan;Xiong Wang;Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology;Key Laboratory for Molecular Diagnosis of Hubei Province,The Central Hospital of Wuhan, Tongji Medical College,Huazhong University of Science and Technology;

【Institution】

Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology;Key Laboratory for Molecular Diagnosis of Hubei Province,The Central Hospital of Wuhan, Tongji Medical College,Huazhong University of Science and Technology;

【Abstract】

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.

【Keywords】

Alzheimer's disease;;Synapse;;Memory;;Sirtuin-1;;microRNA;;Circular RNA

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Total: 24 articles

  • [1] Bin-Lu Sun;Wei-Wei Li;Chi Zhu;Wang-Sheng Jin;Fan Zeng;Yu-Hui Liu;Xian-Le Bu;Jie Zhu;Xiu-Qing Yao;Yan-Jiang Wang;Department of Neurology, Daping Hospital, Third Military Medical University;State Key Laboratory of Trauma, Burn and Combined Injury,Institute of Surgery Research, Daping Hospital, Third Military Medical University;, Clinical Research on Alzheimer's Disease: Progress and Perspectives, Neuroscience Bulletin,
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  • [4] Marcia N. Gordon;;Leigh A. Holcomb;;Paul T. Jantzen;;Giovanni DiCarlo;;Donna Wilcock;;Kristal W. Boyett;;Karen Connor;;Jason Melachrino;;James P. O'Callaghan;;Dave Morgan, Time Course of the Development of Alzheimer-like Pathology in the Doubly Transgenic PS1+APP Mouse, Experimental Neurology,

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