The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA.
The Zucker Hillside Hospital, The Feinstein Institute for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York, USA.
J Neurochem. 2019 Jan;148(1):127-135. doi: 10.1111/jnc.14593. Epub 2018 Nov 12.
In Alzheimer's disease, the phosphorylation of tau is a critical event preceding the formation of neurofibrillary tangles. Previous work exploring the impact of a dopamine blocking antipsychotic on tau phosphorylation in a tau transgenic model suggested that extracellular dopamine may play a regulatory role in the phosphorylation state of tau. In order to test this hypothesis, and in order to develop a mouse model of impaired dopamine metabolism and tauopathy, an extant P301L transgenic tau model of Alzheimer's disease and a novel P301L/catechol-O-methyltransferase deleted model (DM mouse) were treated with the norepinephrine reuptake inhibitor reboxetine, and prefrontal dopamine concentrations and the phosphorylated state of tau was quantified. In two experiments, male and female P301L+/+//COMT+/+ and P301L+/+//COMT-/- (DM) mice were treated with reboxetine 20 mg/kg IP. In one experiment, acutely following reboxetine injection, the prefrontal cortex of mice were microdialyzed for dopamine, and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, utilizing the MetaQuant technique. In another experiment, acutely following reboxetine injections, tau phosphorylation was quantified in the frontal cortex, striatum, and hippocampus of the mice. Reboxetine injections were followed by significant increases from baseline in extracellular dopamine concentrations in P301L and DM mice, with significantly higher peak levels in the DM mice. Treatment was also followed by increases in tau phosphorylation spread throughout brain regions, with a larger impact on female mice. Extracellular dopamine concentrations exert an influence on the phosphorylation state of tau, with surges in dopamine associating with acute increases in tau phosphorylation.
在阿尔茨海默病中，tau 的磷酸化是形成神经原纤维缠结的关键事件。先前的研究探索了一种多巴胺阻断型抗精神病药物对tau 转基因模型中 tau 磷酸化的影响，表明细胞外多巴胺可能在 tau 的磷酸化状态中发挥调节作用。为了验证这一假设，并开发一种多巴胺代谢和 tau 病受损的小鼠模型，我们用去甲肾上腺素再摄取抑制剂瑞波西汀处理现有的 P301L 转基因 tau 型阿尔茨海默病模型和一种新的 P301L/儿茶酚-O-甲基转移酶缺失模型（DM 小鼠），并定量检测前额叶多巴胺浓度和 tau 的磷酸化状态。在两项实验中，雄性和雌性 P301L+/+//COMT+/+和 P301L+/+//COMT-/-（DM）小鼠分别用瑞波西汀 20mg/kg 腹腔注射处理。在一项实验中，在瑞波西汀注射后立即对小鼠的前额叶皮层进行微透析，以利用 MetaQuant 技术检测多巴胺及其代谢物 3,4-二羟基苯乙酸和高香草酸。在另一项实验中，在瑞波西汀注射后立即定量检测小鼠前额叶皮层、纹状体和海马中的 tau 磷酸化。瑞波西汀注射后，P301L 和 DM 小鼠的细胞外多巴胺浓度从基线显著升高，DM 小鼠的峰值水平显著更高。治疗后，tau 磷酸化在整个脑区也增加，对雌性小鼠的影响更大。细胞外多巴胺浓度对 tau 的磷酸化状态有影响，多巴胺的激增与 tau 磷酸化的急性增加有关。
