A single nucleotide polymorphism in primary-microRNA-146a reduces the expression of mature microRNA-146a in patients with Alzheimers disease and is associated with the pathogenesis of Alzheimers disease

摘要

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia among the aging population. Although the incidence of the disease continues to increase, no cure has been developed. Effective treatment is restricted not only due to the lack of curative medicine, but also due to limited understanding of the underlying mechanisms and the diffculties in accurately diagnosing AD in its earliest stages prior to clinical symptoms. Micro (mi) RNAs (miR) have gained increasing attention in the investigation of neurodegenerative diseases. Previous reports have demonstrated that deregulation of miR-146a-5p is associated with the pathogenesis of human AD. In the present study, the coding region of primary (pri)-miR-146a in patients with AD was scanned and the rare C allele of rs2910164 was found to be associated with AD. Using reverse transcription quantitative polymerase chain reaction, it was demonstrated that site variation reduced the expression of mature miR-146a-5p. Notably, a reduction in the expression of miR-146a-5p led to less effcient inhibition of target genes, including Toll-like receptor (TLR)2, which is important in the pathogenesis of AD. Biological function investigations in RAW264.7 cells indicated that, compared with the G allele, the rare C allele upregulated the expression of tumor necrosis factor-α following stimulation with β-amyloid. These findings suggested that one common polymorphism in pri-miR-146a may contribute to the genetic predisposition to AD by disrupting the production of miR-146a-5p and affecting the expression and function of TLR2.