Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies.
Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies.
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DOI：
10.1038/s41598-020-77210-y
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发表时间：
2020-11-23
影响因子：
4.6
通讯作者：
Longo FM
中科院分区：
文献类型：
--
作者：
Yang T;Tran KC;Zeng AY;Massa SM;Longo FM
纵向临床前和临床研究表明，Aβ通过一系列tau依赖性和非依赖性机制驱动神经突和突触变性。由p75神经营养因子受体（p75 NTR）调节的细胞内信号传导网络与与Aβ和tau相关的信号传导网络基本重叠。在这里，我们研究的假设，p75 NTR的调节将抑制多种潜在的致病性tau蛋白的产生和相关的信号，以保护树突棘和过程从Aβ诱导的损伤。在体外暴露于寡聚Aβ的神经元和APP突变小鼠模型中，发现使用小分子LM 11 A-31调节p75 NTR信号传导可抑制Aβ相关的神经突和棘变性;以及tau磷酸化、切割、寡聚化和错误分选。与对tau的这些作用一致，LM 11 A-31抑制Fyn激酶及其靶标tau和NMDA-NR 2B的过度活化，并降低Rho激酶信号传导变化和下游异常的cofilin磷酸化。用假过度磷酸化的tau和组成型活性RhoA进行的体外研究表明，LM 11 A-31可能主要作用于tau磷酸化的上游，并且具有防止RhoA激活的上游和下游的棘丢失的作用。这些发现支持了这样的假设，即p75 NTR信号转导的调节抑制了广谱的Aβ触发的tau相关分子病理学，从而有助于突触弹性。
Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.
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影响因子：
16.2
作者：
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通讯作者：
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影响因子：
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通讯作者：
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25
作者：
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通讯作者：
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