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Plasma BDNF Levels Following Transcranial Direct Current Stimulation Allow Prediction of Synaptic Plasticity and Memory Deficits in 3×Tg-AD Mice.
Frontiers in Cell and Developmental Biology ( IF 4.6 ) Pub Date : 2020-06-09 , DOI: 10.3389/fcell.2020.00541
Sara Cocco 1 , Marco Rinaudo 1 , Salvatore Fusco 1, 2 , Valentina Longo 1 , Katia Gironi 1 , Pietro Renna 1 , Giuseppe Aceto 1 , Alessia Mastrodonato 1 , Domenica Donatella Li Puma 1, 2 , Maria Vittoria Podda 1, 2 , Claudio Grassi 1, 2
Affiliation  

Early diagnosis of Alzheimer’s disease (AD) supposedly increases the effectiveness of therapeutic interventions. However, presently available diagnostic procedures are either invasive or require complex and expensive technologies, which cannot be applied at a larger scale to screen populations at risk of AD. We were looking for a biomarker allowing to unveil a dysfunction of molecular mechanisms, which underly synaptic plasticity and memory, before the AD phenotype is manifested and investigated the effects of transcranial direct current stimulation (tDCS) in 3×Tg-AD mice, an experimental model of AD which does not exhibit any long-term potentiation (LTP) and memory deficits at the age of 3 months (3×Tg-AD-3M). Our results demonstrated that tDCS differentially affected 3×Tg-AD-3M and age-matched wild-type (WT) mice. While tDCS increased LTP at CA3-CA1 synapses and memory in WT mice, it failed to elicit these effects in 3×Tg-AD-3M mice. Remarkably, 3×Tg-AD-3M mice did not show the tDCS-dependent increases in pCREBSer133 and pCaMKIIThr286, which were found in WT mice. Of relevance, tDCS induced a significant increase of plasma BDNF levels in WT mice, which was not found in 3×Tg-AD-3M mice. Collectively, our results showed that plasticity mechanisms are resistant to tDCS effects in the pre-AD stage. In particular, the lack of BDNF responsiveness to tDCS in 3×Tg-AD-3M mice suggests that combining tDCS with dosages of plasma BDNF levels may provide an easy-to-detect and low-cost biomarker of covert impairment of synaptic plasticity mechanisms underlying memory, which could be clinically applicable. Testing proposed here might be useful to identify AD in its preclinical stage, allowing timely and, hopefully, more effective disease-modifying interventions.



中文翻译:

经颅直流电刺激后血浆BDNF水平可预测3xTg-AD小鼠的突触可塑性和记忆障碍。

据推测,阿尔茨海默氏病(AD)的早期诊断可以提高治疗干预的有效性。然而,当前可用的诊断程序是侵入性的或需要复杂且昂贵的技术,其不能大规模地用于筛查具有AD风险的人群。我们正在寻找一种生物标志物,以揭示在AD表型出现之前分子机制的功能异常,突触可塑性和记忆力低下的情况,并研究经颅直流电刺激(tDCS)对3×Tg-AD小鼠的影响,这是一项实验性研究在3个月大时不显示任何长期增强(LTP)和记忆缺陷的AD模型(3×Tg-AD-3M)。我们的结果表明,tDCS差异性地影响了3xTg-AD-3M和年龄匹配的野生型(WT)小鼠。尽管tDCS增加了WT小鼠在CA3-CA1突触和记忆中的LTP,但未能在3xTg-AD-3M小鼠中引发这些效应。值得注意的是,3xTg-AD-3M小鼠在pCREB中未显示tDCS依赖性增加丝氨酸133 和pCaMKII苏氨酸286,这是在WT小鼠中发现的。与此相关的是,tDCS诱导了WT小鼠血浆BDNF水平的显着增加,而在3xTg-AD-3M小鼠中则没有。总体而言,我们的结果表明,可塑性机制在AD前阶段对tDCS的作用具有抵抗力。特别是,在3xTg-AD-3M小鼠中BDNF缺乏对tDCS的响应性表明,将tDCS与血浆BDNF剂量结合可以提供一种易于检测且低成本的生物标记,隐蔽地破坏突触可塑性机制记忆,可能在临床上适用。此处提出的测试可能有助于在临床前阶段识别AD,从而可以进行及时,希望更有效的疾病缓解干预措施。

更新日期:2020-07-03
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