Reduction in CHT1-mediated choline uptake in primary neurons from presenilin-1 M146V mutant knock-in mice.
Reduction in CHT1-mediated choline uptake in primary neurons from presenilin-1 M146V mutant knock-in mice.
复制标题
Presenilin-1 M146V 突变敲入小鼠原代神经元中 CHT1 介导的胆碱摄取减少。
DOI：
10.1016/j.brainres.2006.12.005
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发表时间：
2007
期刊：
影响因子：
2.9
通讯作者：
Guo,Qing
中科院分区：
文献类型：
--
作者：
Payette,DanielJ;Xie,Jun;Guo,Qing
阿尔茨海默病(AD)的记忆丧失与胆碱能活动不足有关。早老素-1(PS-1)的突变可能调节胆碱能信号，尽管它们在AD胆碱能神经传递中的确切作用尚不清楚。神经元通过高亲和力胆碱转运体(CHT1)摄取胆碱是胆碱能神经传递所必需的。CHT1是一种钠离子依赖、半胱氨酸-3(HC-3)敏感的胆碱转运蛋白。虽然Meynert基底核中的胆碱能神经元是大脑皮层胆碱能投射的主要来源，但尚不清楚皮质神经元是否表现出在AD时改变的固有CHT1活性。我们现在报道，初级皮质神经元表达固有的和生物活性的CHT1，在这些神经元中，CHT1介导的胆碱摄取活性在PS-1M146V突变敲入小鼠中显著降低。用HC-3结合和细胞表面生物素化分析进一步的动力学研究表明，PS-1突变通过降低CHT1的配体结合亲和力而抑制CHT1介导的胆碱摄取，而不显著改变质膜上CHT1的表达水平。由于人类新皮质最近被证明具有内源性胆碱能神经支配，我们的结果表明，皮质神经元中CHT1介导的高亲和力胆碱摄取的改变可能与阿尔茨海默病的发生有关。
The memory loss in Alzheimer's disease (AD) has been linked to cholinergic hypoactivity. Mutations in presenilin-1 (PS-1) may regulate cholinergic signaling, although their precise roles in cholinergic neurotransmission in AD are unsettled. Neuronal uptake of choline via the high affinity choline transporter (CHT1) is essential for cholinergic neurotransmission. CHT1 is a Na+-dependent, hemicholinium-3 (HC-3)-sensitive choline transporter. Although cholinergic neurons in the nucleus basalis of Meynert are a major source of cholinergic projections for the cerebral cortex, it is unclear whether cortical neurons exhibit intrinsic CHT1 activity that is altered in AD. We now report that primary cortical neurons express intrinsic and biologically active CHT1, and that, in these neurons, CHT1-mediated choline uptake activity is significantly reduced in PS-1 M146V mutant knock-in mice. Further kinetic studies using HC-3 binding and cell surface biotinylation assays showed that the PS-1 mutation inhibits CHT1 mediated choline uptake by reducing the ligand binding affinity of CHT1 without significantly altering levels of CHT1 expression in the plasma membrane. Since human neocortex has recently been shown to possess intrinsic cholinergic innervation, our results indicate that alterations in CHT1-mediated high affinity choline uptake in cortical neurons may contribute to Alzheimer's dementia.