Ethanol sustains phosphorylated tau protein in the cultured neonatal rat hippocampus: Implications for fetal alcohol spectrum disorders.
Ethanol sustains phosphorylated tau protein in the cultured neonatal rat hippocampus: Implications for fetal alcohol spectrum disorders.
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DOI：
10.1016/j.alcohol.2022.07.007
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发表时间：
2022-09
期刊：
影响因子：
2.3
通讯作者：
Prendergast, Mark Alan
中科院分区：
文献类型：
--
作者：
Bailey, Caleb Seth;Jagielo-Miller, Julia Elaine;Keller, Peggy Sue;Glaser, Ethan Phares;Wilcox, Abigail Lowe;Prendergast, Mark Alan
关键词：
胎儿酒精谱系障碍（FASD）由产前酒精暴露引起的发育，行为和认知异常组成，影响估计2%-5%的儿童，每年在美国花费40亿美元。虽然一些行为疗法有帮助，但支持FASD的神经生物学机制需要进一步阐明，以开发有效的药物治疗。海马体中tau蛋白的作用可能与此有关。Tau在发育中的神经元中催化微管聚合。然而，这种功能可能会被过度磷酸化破坏。在神经退行性tau蛋白病中观察到的许多认知缺陷在某种程度上与在青少年发育障碍中观察到的认知缺陷重叠，例如FASD（例如，选择性记忆、执行功能障碍）。因此，tau蛋白磷酸化可能是FASD功能障碍的一个重要机制。本研究的目的是提供一个经验基础的tau蛋白表征FASD。为此，在出生后第10天（PND 10）从大鼠中提取海马切片;然后将海马切片在体外6天（DIV）和11 DIV之间暴露于50 mM乙醇中5天。在12 DIV和24 DIV时对总Tau和p-Tau（苏氨酸231）进行免疫印迹。在12 DIV和24 DIV下拍摄p-Tau（苏氨酸231）的免疫组织化学荧光图像。对角氨1（CA 1）、CA 3和齿状回（DG）进行单独的p-Tau测量。无论乙醇条件如何，总Tau蛋白表达在12 DIV和24 DIV之间保持不变。在对照组中，较长的DIV与降低的p-Tau相关。然而，在乙醇暴露组中，p-Tau在整个DIV中持续存在。这是第一项研究表明，乙醇暴露维持tau苏氨酸231磷酸化在围产期海马体中，无论总Tau表达。这些发现可能会导致创新的药物靶点，用于治疗FASD中的认知缺陷。
Fetal Alcohol Spectrum Disorders (FASDs) are comprised of developmental, behavioral, and cognitive abnormalities caused by prenatal alcohol exposure, affecting an estimated 2%–5% of children and costing $4 billion annually in the United States. While some behavioral therapies help, the neurobiological mechanisms that underpin FASDs need further elucidation for development of effective pharmacotherapeutics. The role of the tau protein in the hippocampus is likely to be involved. Tau catalyzes microtubule polymerization in developing neurons. However, this function can become disrupted by hyperphosphorylation. Many of the cognitive deficits observed in neurodegenerative tauopathies overlap to some degree with what is observed in juvenile developmental disabilities, such as FASDs (e.g., selective memory, executive dysfunction). Thus, tau protein phosphorylation may be one important mechanism of dysfunction in FASDs. The purpose of this study is to provide an empirical basis for a tauopathic characterization of FASDs. To do so, hippocampal slices were extracted from rats at postnatal day 10 (PND10); hippocampal slices were then exposed to 5 days of 50-mM ethanol between 6 days in vitro (DIV) and 11DIV. Immunoblots were taken for Total and p-Tau (Threonine231) at 12DIV and 24DIV. Immunohistochemical fluorescent images were taken for p-Tau (Threonine231) at 12DIV and 24DIV. Separate p-Tau measures were taken for the cornu ammonis 1 (CA1), CA3, and dentate gyrus (DG). Total Tau protein expression remained unchanged between 12DIV and 24DIV regardless of ethanol condition. In the control group, longer DIV was associated with decreased p-Tau. However, in the ethanol-exposed group, p-Tau was sustained across DIV. This is the first study to show that ethanol exposure sustains tau Threonine231 phosphorylation in the perinatal hippocampus regardless of Total Tau expression. These findings could lead to innovative pharmacotherapeutic targets for the treatment of cognitive deficits seen in FASDs.
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影响因子：
4.8
作者：
Kazim SF;Chuang SC;Zhao W;Wong RK;Bianchi R;Iqbal K
通讯作者：
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DOI：
10.1002/ajmg.c.30015
发表时间：
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