Aβ/tau oligomer interplay at human synapses supports shifting therapeutic targets for Alzheimer's disease.
Aβ/tau oligomer interplay at human synapses supports shifting therapeutic targets for Alzheimer's disease.
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DOI：
10.1007/s00018-022-04255-9
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发表时间：
2022-04-04
期刊：
影响因子：
--
通讯作者：
Taglialatela G
中科院分区：
文献类型：
--
作者：
Marcatti M;Fracassi A;Montalbano M;Natarajan C;Krishnan B;Kayed R;Taglialatela G
阿尔茨海默病（AD）的特征在于由于淀粉样蛋白β（AβO）和tau蛋白（TauO）的毒性寡聚体累积的突触损伤而导致的进行性认知下降。越来越多的人认为，阻止这些寡聚体与突触相互作用可能是治疗AD的有效方法。然而，最近的临床试验失败表明，在晚期AD中靶向Aβ的有效性较低。研究人员已经将注意力转向TauO，因为该物种的水平在疾病发病机制后期增加。在这里，我们表明，AβO和TauO差异靶向突触，并影响彼此的结合动力学。使用流式细胞术和蛋白质印迹分析评价了标记的预形成Aβ和tau寡聚体与从小鼠和死后认知完整的老年人大脑的海马和额叶皮质分离的突触体的结合。使用免疫荧光测定法评估标记的预形成Aβ和tau寡聚体与小鼠原代神经元的结合。单突触长时程增强荧光分析法（FASS-LTP）检测突触功能障碍。我们证明，较高的TauO浓度有效地胜过AβO，成为突触相关的主要物质。相反，高浓度的AβO促进突触TauO募集。小鼠原代皮层神经元的免疫荧光分析证实了AβO和TauO的差异突触结合动力学。此外，使用ICV注射AβO或TauO的老年3xTgAD小鼠的体内实验完全支持这些发现。与这些观察结果一致，FASS-LTP分析表明，AβO加剧了TauO诱导的化学LTP抑制。最后，用蛋白酶K预消化消除了TauO竞争AβO的能力，而不影响高水平AβO增加突触TauO募集的能力。因此，与AβO不同，TauO对突触体的作用受到膜中蛋白质底物缺乏的阻碍。这些结果引入了TauO成为AD晚期主要突触毒性物质的概念，从而支持了TauO可能是临床表现AD最有效的治疗靶点的假设。 在线版本包含补充材料，可通过10.1007/s 00018 -022-04255-9获得。
Alzheimer’s disease (AD) is characterized by progressive cognitive decline due to accumulating synaptic insults by toxic oligomers of amyloid beta (AβO) and tau (TauO). There is growing consensus that preventing these oligomers from interacting with synapses might be an effective approach to treat AD. However, recent clinical trial failures suggest low effectiveness of targeting Aβ in late-stage AD. Researchers have redirected their attention toward TauO as the levels of this species increase later in disease pathogenesis. Here we show that AβO and TauO differentially target synapses and affect each other's binding dynamics. Binding of labeled, pre-formed Aβ and tau oligomers onto synaptosomes isolated from the hippocampus and frontal cortex of mouse and postmortem cognitively intact elderly human brains was evaluated using flow-cytometry and western blot analyses. Binding of labeled, pre-formed Aβ and tau oligomers onto mouse primary neurons was assessed using immunofluorescence assay. The synaptic dysfunction was measured by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP) assay. We demonstrated that higher TauO concentrations effectively outcompete AβO and become the prevailing synaptic-associated species. Conversely, high concentrations of AβO facilitate synaptic TauO recruitment. Immunofluorescence analyses of mouse primary cortical neurons confirmed differential synaptic binding dynamics of AβO and TauO. Moreover, in vivo experiments using old 3xTgAD mice ICV injected with either AβO or TauO fully supported these findings. Consistent with these observations, FASS-LTP analyses demonstrated that TauO-induced suppression of chemical LTP was exacerbated by AβO. Finally, predigestion with proteinase K abolished the ability of TauO to compete off AβO without affecting the ability of high AβO levels to increase synaptic TauO recruitment. Thus, unlike AβO, TauO effects on synaptosomes are hampered by the absence of protein substrate in the membrane. These results introduce the concept that TauO become the main synaptotoxic species at late AD, thus supporting the hypothesis that TauO may be the most effective therapeutic target for clinically manifest AD. The online version contains supplementary material available at 10.1007/s00018-022-04255-9.
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DOI：
10.1523/jneurosci.0295-20.2020
发表时间：
2021-01-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Fracassi A;Marcatti M;Zolochevska O;Tabor N;Woltjer R;Moreno S;Taglialatela G
通讯作者：
Taglialatela G
DOI：
10.3233/jad-179941
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
通讯作者：
Klein WL
影响因子：
13.1
作者：
Crimins, Johanna L.;Pooler, Amy;Polydoro, Manuela;Luebke, Jennifer I.;Spires-Jones, Tara L.
通讯作者：
Spires-Jones, Tara L.
近红外光处理可降低两种人tauopathies的转基因小鼠模型中有毒tau低聚物的突触水平。
影响因子：
5.1
作者：
Comerota MM;Tumurbaatar B;Krishnan B;Kayed R;Taglialatela G
通讯作者：
Taglialatela G
影响因子：
3
作者：
Franklin, Whitney;Taglialatela, Giulio
通讯作者：
Taglialatela, Giulio