5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.
5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.
复制标题
5-HT4 受体激动剂治疗可减少 PS19 tau 蛋白病小鼠模型中的 tau 蛋白病理学和行为缺陷。
DOI：
10.1101/2023.02.03.526871
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Myeku,Natura
中科院分区：
文献类型：
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作者：
Jiang,Shan;Sydney,EricJ;Runyan,AveryM;Serpe,Rossana;Figueroa,HelenY;Yang,Mu;Myeku,Natura
研究背景在阿尔茨海默病（AD）的早期阶段，tau蛋白在突触中的积累已被证明会导致突触损伤、突触丢失以及tau蛋白病理通过跨突触连接的神经元的扩散。此外，突触丢失与认知功能下降相关，这为研究靶向突触和突触tau的治疗策略以挽救或预防AD中的认知下降提供了机会。其中一个有前途的突触靶点是5-HT 4突触能受体，该受体存在于参与记忆过程的脑结构中的突触后。5-HT 4 R刺激发挥突触发生和促认知作用，涉及突触可塑性所必需的突触-核信号传导。然而，目前尚不清楚5-HT 4 R激活是否具有治疗效果的tau pathology.MethodsThe本研究的目的是调查慢性刺激5-HT 4 R的影响，由两个激动剂，prucalopride和RS-67333，在PS19小鼠，tau蛋白病模型。我们利用梯度测定分离突触前和突触后区室，然后对突触区室和总脑组织中的tau种类和泛素化蛋白进行生化分析。接下来，我们进行动力学测定以测试蛋白酶体在处理条件下的水解能力。此外，行为测试（例如开放野和非母体筑巢测试）用于评估治疗范式中的焦虑样行为和海马相关认知功能。结果我们的结果表明，5-HT 4 R激动减少了tau蛋白病，减少了突触tau蛋白，增加了蛋白酶体活性，并改善了PS19小鼠的认知功能。我们的数据表明，增强的蛋白酶体活性突触介导的信号导致增强的周转tau最初在突触内的受体是本地化，并随着时间的推移，治疗衰减的积累tau聚集和改善的认知功能的PS19 mice. ConclusionSevertheless，5-HT 4 R的刺激提供了一个有前途的治疗，以拯救突触从积累有毒的突触tau，在AD的早期阶段很明显。
BackgroundAccumulation of tau in synapses in the early stages of Alzheimer’s disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of tau pathology through trans-synaptically connected neurons. Moreover, synaptic loss correlates with a decline in cognitive function, providing an opportunity to investigate therapeutic strategies to target synapses and synaptic tau to rescue or prevent cognitive decline in AD. One of the promising synaptic targets is the 5-HT4 serotonergic receptor present postsynaptically in the brain structures involved in the memory processes. 5-HT4R stimulation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tau pathology.MethodsThe goal of this study was to investigate the impact of chronic stimulation of 5-HT4R by two agonists, prucalopride and RS-67333, in PS19 mice, a model of tauopathy. We utilized gradient assays to isolate pre- and post-synaptic compartments, followed by biochemical analyses for tau species and ubiquitinated proteins in the synaptic compartments and total brain tissue. Next, we performed kinetic assays to test the proteasome’s hydrolysis capacity in treatment conditions. Moreover, behavioral tests such as the open field and non-maternal nest-building tests were used to evaluate anxiety-like behaviors and hippocampal-related cognitive functioning in the treatment paradigm.ResultsOur results show that 5-HT4R agonism reduced tauopathy, reduced synaptic tau, increased proteasome activity, and improved cognitive functioning in PS19 mice. Our data suggest that enhanced proteasome activity by synaptic mediated signaling leads to the enhanced turnover of tau initially within synapses where the receptors are localized, and over time, the treatment attenuated the accumulation of tau aggregation and improved cognitive functioning of the PS19 mice.ConclusionTherefore, stimulation of 5-HT4R offers a promising therapy to rescue synapses from the accumulation of toxic synaptic tau, evident in the early stages of AD.