School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK.
Int J Mol Sci. 2022 Jan 5;23(1):554. doi: 10.3390/ijms23010554.
The complete molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpression of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression decreases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice ( = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. and were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of , and in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance.
阿尔茨海默病（AD）病理生理学的完整分子机制仍有待阐明。最近，miR-455-3p 被确定为 AD 的早期循环生物标志物，AD 患者死后脑组织中的表达增加。miR-455-3p 还直接靶向并下调 APP，miR-455-3p 的过表达抑制其毒性作用。在这里，我们表明 miR-455-3p 在野生型小鼠大脑中的表达随年龄增长而降低。我们利用 CRISPR-Cas9 生成了 miR-455 缺失的小鼠，以进一步探索其功能。miR-455 的缺失导致体重增加，可能表明存在代谢紊乱。此外，miR-455 缺失小鼠在新物体识别任务中的表现显著下降（=0.004），表明识别记忆受损。在旷场试验中也捕捉到了轻微的焦虑增加。和被鉴定为 miR-455-3p 的新直接靶标，miR-455-3p 的过表达导致神经母细胞瘤细胞中表达的减少。在 14 个月大的 miR-455 缺失小鼠的海马体中，APP、BACE1 和 TAU 的蛋白水平均升高。这些发现强化了 miR-455 参与 AD 进展的作用，并证明了其对认知表现的作用。
