Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.
Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.
复制标题
受阿尔茨海默病影响的皮质区域高亲和力胆碱转运蛋白的过度表达。
DOI：
10.1172/jci117387
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Seidler,FJ
中科院分区：
文献类型：
--
作者：
Slotkin,TA;Nemeroff,CB;Bissette,G;Seidler,FJ
阿尔茨海默病中的胆碱能缺陷通常通过胆碱乙酰转移酶（合成乙酰胆碱的酶）来评估。然而，乙酰胆碱形成的决定步骤是通过神经终末膜中的高亲和力转运蛋白摄取胆碱。评估摄取是困难的，因为转运蛋白功能的调节变化在死后迅速衰减。为了克服这个问题，将患有或不患有阿尔茨海默病的患者的脑区域在死亡后4小时内冷冻，并检查胆碱乙酰转移酶活性和[3 H]-半胆碱-3与胆碱转运蛋白的结合。与胆碱能投射的丧失相一致，大脑皮层区域的酶活性显著降低，而与阿尔茨海默病无关的壳核区域则未受影响。然而，[3 H]hemicholinium-3结合显着增强皮质区域。在额叶皮层，增加[3 H]hemicholinium-3结合远远超过胆碱乙酰转移酶的损失，表明转运蛋白过度表达超出了抵消突触末端损失所必需的。这些结果表明，在阿尔茨海默氏病中，胆碱能功能的丧失不仅仅是由神经末梢的破坏决定的，而是涉及胆碱利用的额外改变;旨在增加胆碱能神经元活性的干预可能因此加速神经退行性变。
Cholinergic deficits in Alzheimer's disease are typically assessed by choline acetyltransferase, the enzyme that synthesizes acetylcholine. However, the determining step in acetylcholine formation is choline uptake via a high affinity transporter in nerve terminal membranes. Evaluating uptake is difficult because regulatory changes in transporter function decay rapidly postmortem. To overcome this problem, brain regions from patients with or without Alzheimer's disease were frozen within 4 h of death and examined for both choline acetyltransferase activity and for binding of [3H]-hemicholinium-3 to the choline transporter. Consistent with the loss of cholinergic projections, cerebral cortical areas exhibited marked decreases in enzyme activity whereas the putamen, a region not involved in Alzheimer's disease, was unaffected. However, [3H]hemicholinium-3 binding was significantly enhanced in the cortical regions. In the frontal cortex, the increase in [3H]hemicholinium-3 binding far exceeded the loss of choline acetyltransferase, indicating transporter overexpression beyond that necessary to offset loss of synaptic terminals. These results suggest that, in Alzheimer's disease, the loss of cholinergic function is not dictated simply by destruction of nerve terminals, but rather involves additional alterations in choline utilization; interventions aimed at increasing the activity of cholinergic neurons may thus accelerate neurodegeneration.