《生命科学》 2013, 25(11): 1077-1083

囊泡谷氨酸转运体在阿尔兹海默病发病机制中的作用

户东梅^1，2，程肖蕊¹，周文霞^1*，张永祥¹，周立春^2*

(1 军事医学科学院毒物药物研究所，北京 100850；2 首都医科大学附属北京朝阳医院，北京 100043)

摘　要：摘　要：阿尔兹海默病(Alzheimer's disease， AD) 是一种多因素复杂性神经退行性疾病，β 淀粉样蛋白(βamyloid， Aβ) 级联假说和谷氨酸兴奋性毒性是其重要的发病机制。囊泡谷氨酸转运体(vesicular glutamate transporters， VGLUTs) 可特异性地将神经元内的谷氨酸转移入突触囊泡，且一个独立功能单位的VGLUT 对于完成一个囊泡的填充是必要和充分的，没有VGLUT 的突触囊泡中就没有谷氨酸(glutamate， Glu)，VGLUT 在一定程度上决定了释放进突触间隙Glu 的量，是谷氨酸能突触传递的关键因子。在AD 中Aβ增多聚集，VGLUTs 表达减低，且VGLUTs 转运Glu 和Glu 的囊泡释放与淀粉样前体蛋白(amyloid precursor protein， APP) 代谢和Aβ 的释放在突触囊泡的循环中存在行为平行性和共定位。胞外Aβ 的增加可增强囊泡的释放几率，而Glu 引起的突触活性增加亦可增加胞外Aβ 的浓度。APP/Aβ 与谷氨酸能系统之间相互影响导致AD 的发生，VGLUTs 可能在其中发挥重要作用，被认为是治疗AD 的潜在的药物靶点和预警标志物。

VGLUTs in the pathogenesis of Alzheimer's disease

HU Dong-Mei^1，2， CHENG Xiao-Rui¹， ZHOU Wen-Xia^1*， ZHANG Yong-Xiang¹， ZHOU Li-Chun^2*

(1 Institute of Pharmacology and Toxicology， Academy of Military Medical Sciences， Beijing 100850， China; 2 Chao Yang Hospital， Capital Medical University， Beijing 100043， China)

Abstract: Abstract: Alzheimer's disease (AD) is a classic multi-factorial complex neurodegenerative disease. The β amyloid (Aβ) toxicol cascade and glutamate excitotoxicity are of the important pathogenesis of AD. Vesicular glutamate transporters (VGLUTs) can specifically transfer glutamate into the synaptic vesicle. One single functional unit of VGLUT is necessary and sufficient to fill successfully vesicle， and the vesicles without VGLUT are empty. VGLUT determines the amount of glutamate that released into the synaptic cleft in some extent and is the key factor of glutamatergic synaptic transmission. There are extensive deposition of Aβ and reduced expression of VGLUT in the brain of AD patients. The processes of vesicle glutamate release and glutamate transferred by VGLUT are parallel with the Aβ release and amyloid precursor protein (APP) metabolism in the synaptic vesicle cycle. VGLUTs co-localize with APP in synaptic vesicle. The increase in extracellular Aβ enhances the probability of vesicle Glu release， and otherwise the increase in glutamate-induced synaptic activity elevates the extracellular concentration of Aβ. The interaction between APP/Aβ and glutamatergic system induced AD， in which VGLUTs may play an important role. VGLUTs have been considered a potential drug target in the treatment of AD and biomarkers in the early diagnosis of AD.