MiR-149-5p inhibition reduces Alzheimer's disease ?-amyloid generation in 293/APPsw cells by upregulating H4K16ac via KAT8.

ABSTRACT: Alzheimer's disease (AD), the leading cause of age-related dementia, is characterized by abnormal ?-amyloid accumulation. During learning, memory formation and consolidation, increased levels of histone H3 and H4 acetylation are observed. The present study reported significantly decreased level of H4K16ac in the plasma of patients with AD compared with healthy subjects via western blotting and reverse transcription-quantitative (RT-q)PCR. Lysine acetyltransferase 8 (KAT8) expression, the major lysine acetyltransferase responsible for the acetylation of H4K16, was significantly decreased in patients with AD compared with healthy subjects as determined via western blotting and RT-qPCR. The results indicated that aberrant expression patterns of H4K16ac and KAT8 might be associated with AD progression. Moreover, western blot analysis demonstrated that KAT8-overexpression cells displayed increased levels of H4K16ac, accompanied by higher levels of neuroprotective soluble amyloid precursor protein (sAPP)? and ?-secretase (BACE)2, and decreased levels of sAPP? and BACE1 compared with negative control and vector cells. In neurodegenerative disorders, microRNAs (miRNAs/miRs) are deregulated; however, the effect of miRNA dysregulation on histone acetylation is not completely understood. To the best of our knowledge, the present study identified a novel inhibitory interaction between miR-149-5p and KAT8 3'-UTR that contributed to the pathological alterations in an AD cell model for the first time, using bioinformatics and a dual-luciferase reporter assay. The western blotting results indicated that, compared with the inhibitor control group, miR-149-5p inhibitor markedly increased H4K16ac levels, which were significantly suppressed by co-transfection with KAT8 short hairpin (sh)RNA. KAT8 shRNA and miR-149-5p inhibitor co-transfection abolished the beneficial effects of miR-149-5p inhibitor. The results indicated that miR-149-5p regulated KAT8 and H4K16ac expression in an AD cell model, which may be associated with the pathological process of AD; therefore, miRNA may serve as a potential drug target for AD.

SUBMITTER: Chen F 

PROVIDER: S-EPMC7507054 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature