MicroRNAs 99b-5p/100-5p Regulated by Endoplasmic Reticulum Stress are Involved in Abeta-Induced Pathologies

Xiaoyang Ye, Hongxue Luo, Yan Chen, Qi Wu, Yi Xiong, Jinyong Zhu, Yarui Diao, Zhenguo Wu, Jianting Miao, Jun Wan

Alzheimer's disease (AD) is the most common cause of dementia. Amyloid β (Abeta, Aβ) deposition and intracellular tangles are the pathological hallmarks of AD. MicroRNAs (miRNAs) are small non-coding RNAs, which have been found to play very important roles, and have the potential to serve as diagnostic markers during neuronal pathogenesis. In this study, we aimed to determine the roles of miR-99b-5p and miR-100-5p in Aβ-induced neuronal pathologies. We detected the expression levels of miR-99b-5p and miR-100-5p in the brains of APPswe/PS1ΔE9 double-transgenic mice (APP/PS1 mice) at different age stages and found that both miRNAs were decreased at early stages while increased at late stages of APP/PS1 mice when compared with the age-matched wild type (WT) mice. Similar phenomenon was also observed in Aβ-treated cultured cells. We also confirmed that mammalian target of rapamycin (mTOR) is one of the targets of miR-99b-5p/100-5p, which is consistent with previous studies in cancer. MiR-99b-5p/100-5p has been found to promote cell apoptosis with the Aβ treatment. This effect may be induced via the mTOR pathway. In our study, we find both miR-99b-5p and miR-100-5p affect neuron survival by targeting mTOR. We also speculate that dynamic change of miR-99b-5p/100-5p levels during Aβ-associated pathologies might be attributed to Aβ-induced endoplasmic reticulum stress (ER stress), suggesting the potential role of the "ER stress-miRNAs-mTOR" axis in Aβ-related AD pathogenesis.