Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.
Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.
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DOI：
10.1111/jnc.13230
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发表时间：
2015-10
影响因子：
4.7
通讯作者：
Reed MN
中科院分区：
文献类型：
--
作者：
Hunsberger HC;Weitzner DS;Rudy CC;Hickman JE;Libell EM;Speer RR;Gerhardt GA;Reed MN
在被诊断为阿尔茨海默病(AD)之前的几年里，海马体的过度兴奋是AD高危人群中常见的现象。我们以前的工作表明，谷氨酸神经传递的失调可能介导了这种超兴奋性，而谷氨酸调控失调与阿尔茨海默病(TauP301L)4510小鼠模型的认知缺陷有关。为了确定改善谷氨酸调节是否可以减轻认知障碍和AD相关病理，TauP301L小鼠接受了利鲁唑(~12.5 mg/kg/天，P.O.)治疗，这是FDA批准的一种治疗ALS的药物，可以降低细胞外谷氨酸水平。Riluzole治疗的TauP301L小鼠表现出记忆能力的改善，这与海马齿状回(DG)、AM3角(CA3)和CA1区(CA1)谷氨酸释放减少和谷氨酸摄取增加有关。利鲁唑治疗还可减轻TauP301L介导的海马囊泡性谷氨酸转运体(VGLUT1)表达的增加，以及TauP301L介导的海马谷氨酸转运体1(GLT-1)和PSD-95表达的降低。利鲁唑治疗也减轻了tau的病理改变。这些发现进一步阐明了与tau病理相关的谷氨酸调节的变化，并为临床适用的治疗方法的发展打开了新的机会，以调节易患阿尔茨海默病的人的脆弱回路中的谷氨酸。
In the years preceding a diagnosis of Alzheimer’s disease (AD), hyperexcitability of the hippocampus is a commonly observed phenomenon in those at risk for AD. Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for ALS that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved memory performance that was associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole treatment also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1) and PSD-95 expression. Riluzole treatment also reduced tau pathology. These findings further elucidate the changes in glutamate regulation associated with tau pathology and open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.