The toxicity of tumor necrosis factor-alpha upon cholinergic neurons within the nucleus basalis and the role of norepinephrine in the regulation of inflammation: implications for Alzheimer's disease.
The toxicity of tumor necrosis factor-alpha upon cholinergic neurons within the nucleus basalis and the role of norepinephrine in the regulation of inflammation: implications for Alzheimer's disease.
复制标题
肿瘤坏死因子-α 对基底核内胆碱能神经元的毒性以及去甲肾上腺素在炎症调节中的作用：对阿尔茨海默病的影响。
DOI：
10.1016/s0306-4522(03)00545-1
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发表时间：
2003
期刊：
影响因子：
3.3
通讯作者：
Rosi,S
中科院分区：
文献类型：
--
作者：
Wenk,GL;McGann,K;Hauss-Wegrzyniak,B;Rosi,S
炎症和前脑去甲肾上腺素减少是阿尔茨海默病的特征，它们可能相互作用，导致特定神经系统的退化。我们在基底前脑胆碱能系统内重现了这些情况，该区域易受阿尔茨海默病退化的影响。将肿瘤坏死因子-α注入用去甲肾上腺素神经元毒素N-（2-氯乙基）-N-乙基-2-溴苄胺（DSP 4）预处理的年轻小鼠基底前脑，预期去甲肾上腺素能输入的丧失将增加胆碱能神经元的丧失。结果表明，单独慢性输注肿瘤坏死因子-α可显著降低皮质胆碱乙酰转移酶活性，并增加基底前脑内活化的小胶质细胞和星形胶质细胞的数量。用DSP 4全身治疗后前脑去甲肾上腺素的损失没有改变皮质胆碱乙酰转移酶活性的水平或激活小胶质细胞，但显著激活基底前脑内的星形胶质细胞。将肿瘤坏死因子-α输注到DSP 4预处理的小鼠中也降低了输注侧的皮质胆碱乙酰转移酶活性;然而，这种下降并不显著大于单独输注肿瘤坏死因子-α产生的下降。观察到的神经变性可能是间接的，因为双重免疫荧光研究未发现基底前脑胆碱乙酰转移酶阳性细胞上肿瘤坏死因子-α I型受体共存的证据。结果表明，去甲肾上腺素能细胞的损失在阿尔茨海默氏病并没有增加慢性神经炎症的后果，并没有增强前脑胆碱能神经元的神经变性。
Inflammation and reduced forebrain norepinephrine are features of Alzheimer's disease that may interact to contribute to the degeneration of specific neural systems. We reproduced these conditions within the basal forebrain cholinergic system, a region that is vulnerable to degeneration in Alzheimer's disease. Tumor necrosis factor-α was infused into the basal forebrain of young mice pretreated with a norepinephrine neuronal toxin, N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4), with the expectation that the loss of noradrenergic input would enhance the loss of cholinergic neurons. The results indicate that chronic infusion of tumor necrosis factor-α alone significantly decreased cortical choline acetyltransferase activity and increased the number of activated microglia and astrocytes within the basal forebrain. The loss of forebrain norepinephrine following systemic treatment with DSP4 did not alter the level of cortical choline acetyltransferase activity or activate microglia but significantly activated astrocytes within the basal forebrain. Infusion of tumor necrosis factor-α into DSP4-pretreated mice also reduced cortical choline acetyltransferase activity on the side of the infusion; however, the decline was not significantly greater than that produced by the infusion of tumor necrosis factor-α alone. The neurodegeneration seen may be indirect since a double-immunofluorescence investigation did not find evidence for the co-existence of tumor necrosis factor-α type I receptors on choline acetyltransferase-positive cells in the basal forebrain. The results suggest that noradrenergic cell loss in Alzheimer's disease does not augment the consequences of the chronic neuroinflammation and does not enhance neurodegeneration of forebrain cholinergic neurons.