Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.
Mol Neurobiol. 2018 Jul;55(7):6007-6020. doi: 10.1007/s12035-017-0820-z. Epub 2017 Nov 13.
Aggregation of amyloid-β (Aβ) peptides, which are the cleavage products of amyloid precursor protein (APP), is a major pathological hallmark in the brain of Alzheimer's disease (AD). Now, we know little about the roles of APP translation in the disease progression of AD. Here, we show that BC1, a long noncoding RNA (lncRNA), is expressed in the brain of AD mice. BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks aggregation of Aβ in the brain and protects against the spatial learning and memory deficits. Expression of exogenous BC1 in excitatory pyramidal neurons of mice induces Aβ peptides accumulation and the spatial learning and memory impairments. This study provides a novel mechanism underlying aggregation of Aβ peptides via BC1 induction of APP mRNA translation and hence warrants a promising target for AD therapy.
淀粉样蛋白-β (Aβ) 肽的聚集是阿尔茨海默病 (AD) 患者大脑中的主要病理标志，这些肽是淀粉样前体蛋白 (APP) 的裂解产物。目前，我们对 APP 翻译在 AD 疾病进展中的作用知之甚少。在这里，我们发现长非编码 RNA (lncRNA) BC1 在 AD 小鼠的大脑中表达。BC1 通过与脆性 X 综合征蛋白 (FMRP) 结合诱导 APP mRNA 的翻译。在 AD 小鼠中抑制 BC1 或 BC1-FMRP 结合可阻止脑内 Aβ的聚集，并预防空间学习和记忆缺陷。在小鼠兴奋性锥体神经元中外源表达 BC1 可诱导 Aβ 肽的积累以及空间学习和记忆障碍。本研究提供了一个通过 BC1 诱导 APP mRNA 翻译导致 Aβ 肽聚集的新机制，因此为 AD 治疗提供了一个有前途的靶点。
