Increased tau phosphorylation follows impeded dopamine clearance in a P301L and novel P301L/COMT-deleted (DM) tau mouse model.
Increased tau phosphorylation follows impeded dopamine clearance in a P301L and novel P301L/COMT-deleted (DM) tau mouse model.
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DOI：
10.1111/jnc.14593
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发表时间：
2019-01
影响因子：
4.7
通讯作者：
Davies P
中科院分区：
文献类型：
--
作者：
Koppel J;Jimenez H;Adrien L;H Chang E;Malhotra AK;Davies P
在阿尔茨海默病中，tau的磷酸化是神经原纤维缠结形成之前的一个关键事件。先前在tau转基因模型中探索多巴胺阻断抗精神病药物对tau磷酸化的影响的工作表明，细胞外多巴胺可能在tau的磷酸化状态中发挥调节作用。为了验证这一假说，并为了建立多巴胺代谢受损和相互作用的小鼠模型，用去甲肾上腺素再摄取抑制剂瑞波西汀治疗现有的P301L转基因的阿尔茨海默病tau模型和一种新的P301L/儿茶酚-O-甲基转移酶缺失模型(DM小鼠)，并定量测定前额叶的多巴胺浓度和tau的磷酸化状态。在两个实验中，雄性和雌性P301L+/+/COMT+/+和P301L+/+/COMT−/−(DM)小鼠ip瑞波西汀20 mg/kg。在一项实验中，在注射瑞波西汀后，利用MetaQuant技术，对小鼠的前额叶皮质进行了多巴胺及其代谢物3，4-二羟基苯乙酸和高香草酸的微透析。在另一项实验中，在注射瑞波西汀后，tau的磷酸化在小鼠的额叶皮质、纹状体和海马区被量化。注射瑞波西汀后，P301L和DM小鼠细胞外多巴胺浓度较基线显著增加，其中DM小鼠的峰值水平明显更高。治疗之后，tau的磷酸化水平也增加了，分布在整个大脑区域，对雌性小鼠的影响更大。细胞外多巴胺浓度对tau的磷酸化状态产生影响，与tau磷酸化急剧增加相关的多巴胺激增。
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.
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影响因子：
12.7
作者：
Janocko NJ;Brodersen KA;Soto-Ortolaza AI;Ross OA;Liesinger AM;Duara R;Graff-Radford NR;Dickson DW;Murray ME
通讯作者：
Murray ME
影响因子：
2.5
作者：
Ihalainen, JA;Riekkinen, P;Feenstra, MGP
通讯作者：
Feenstra, MGP
影响因子：
30.8
作者：
Lewis, J;McGowan, E;Hutton, M
通讯作者：
Hutton, M
影响因子：
4.2
作者：
Acker, Christopher M.;Forest, Stefanie K.;d'Abramo, Cristina
通讯作者：
d'Abramo, Cristina
DOI：
10.1073/pnas.1831768100
发表时间：
2003-09-16
影响因子：
11.1
作者：
Cyr, M;Beaulieu, JM;Caron, MG
通讯作者：
Caron, MG