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Cognitive Decline and Modulation of Alzheimer's Disease-Related Genes After Inhibition of MicroRNA-101 in Mouse Hippocampal Neurons.
Molecular Neurobiology ( IF 5.1 ) Pub Date : 2020-06-05 , DOI: 10.1007/s12035-020-01957-8
C Barbato 1, 2 , G Giacovazzo 3 , F Albiero 4 , R Scardigli 5, 6 , C Scopa 6 , M T Ciotti 1 , G Strimpakos 1 , R Coccurello 3, 7 , F Ruberti 1
Affiliation  

MicroRNAs have emerged as regulators of brain development and function. Reduction of miR-101 expression has been reported in rodent hippocampus during ageing, in the brain of Alzheimer’s disease (AD) patients and in AD animal models. In this study, we investigated the behavioral and molecular consequences of inhibition of endogenous miR-101 in 4–5-month-old C57BL/6J mice, infused with lentiviral particles expressing a miR-101 sponge (pLSyn-miR-101 sponge) in the CA1 field of the hippocampus. The sponge-infected mouse model showed cognitive impairment. The pLSyn-miR-101 sponge-infected mice were unable to discriminate either a novel object location or a novel object as assessed by object place recognition (OPR) and novel object recognition (NOR) tasks, respectively. Moreover, the sponge-infected mice evaluated for contextual memory in inhibitory avoidance task showed shorter retention latency compared to control pLSyn mice. These cognitive impairment features were associated with increased hippocampal expression of relevant miR-101 target genes, amyloid precursor protein (APP), RanBP9 and Rab5 and overproduction of amyloid beta (Aβ) 42 levels, the more toxic species of Aβ peptide. Notably, phosphorylation-dependent AMP-activated protein kinase (AMPK) hyperactivation is associated with AD pathology and age-dependent memory decline, and we found AMPK hyperphosphorylation in the hippocampus of pLSyn-miR-101 sponge mice. This study demonstrates that mimicking age-associated loss of miR-101 in hippocampal neurons induces cognitive decline and modulation of AD-related genes in mice.



中文翻译:

小鼠海马神经元中MicroRNA-101抑制后,与阿尔茨海默氏病相关基因的认知下降和调节。

MicroRNA已成为大脑发育和功能的调节剂。据报道,衰老期间啮齿类动物海马,阿尔茨海默氏病(AD)患者的大脑和AD动物模型中miR-101表达的降低。在这项研究中,我们研究了内源性miR-101在4-5个月大的C57BL / 6J小鼠中的行为和分子后果,该小鼠注入了表达miR-101海绵的慢病毒颗粒(pLSyn-miR-101海绵)。海马CA1区域。海绵感染的小鼠模型显示出认知障碍。pLSyn-miR-101海绵感染的小鼠无法分别通过对象位置识别(OPR)和新对象识别(NOR)任务来区分新对象的位置或新对象。此外,与抑制性pLSyn小鼠相比,在抑制回避任务中评估了情境记忆的海绵感染小鼠显示出更短的保留潜伏期。这些认知障碍特征与相关miR-101靶基因,淀粉样蛋白前体蛋白(APP),RanBP9和Rab5的海马表达增加以及淀粉样蛋白β(Aβ)42水平的生产过量有关,后者是Aβ肽的毒性更大的物种。值得注意的是,磷酸化依赖的AMP活化蛋白激酶(AMPK)过度活化与AD病理和年龄依赖性记忆衰退有关,我们发现pLSyn-miR-101海绵小鼠海马中AMPK过度磷酸化。这项研究表明,模仿海马神经元中与年龄相关的miR-101缺失会诱导小鼠认知功能下降和AD相关基因的调节。

更新日期:2020-06-05
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