Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer's disease
Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer's disease
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DOI：
10.1016/j.neuroscience.2004.11.047
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发表时间：
2005-01-01
期刊：
影响因子：
3.3
通讯作者：
Hamel, E
中科院分区：
文献类型：
--
作者：
Aucoin, JS;Jiang, P;Hamel, E
阿尔茨海默病（AD）的特征在于淀粉样蛋白-β（AP）肽增加、神经元缠结、氧化应激和胆碱能缺陷。然而，这些缺陷的选择性及其与AP病理或氧化应激的关系仍不清楚。因此，我们研究了淀粉样变性相关的变化，乙酰胆碱（ACh）和5-羟色胺（5-HT）的神经支配的海马和顶叶皮层的胆碱乙酰转移酶（ChAT）和5-HT免疫细胞化学，在6，12/14和18个月大的转基因小鼠携带家族性AD连锁突变（hAPP（Sw，Ind））。此外，使用锰超氧化物歧化酶（MnSOD）和硝基酪氨酸免疫反应性为标志物，我们评估了氧化应激和ACh赤字在18个月大的小鼠之间的关系。在所有年龄段的两个区域都观察到硫磺素阳性AP斑块;它们在海马中数量更多，数量增加（> 15倍），大小作为年龄的函数。大多数斑块表现出或被MnSOD免疫反应性增加所包围，在其附近可见营养不良的ACh或5-HT轴突。免疫反应性轴突静脉曲张的计数显示ACh神经支配显着减少，5-HT的保留，即使在老年小鼠。首先在海马中明显，ACh末端的损失在12/14个月时约为20%，在18个月时并不显著更大（26%）。在顶叶皮质中，ACh去神经支配仅在18个月时才显着，不同层的平均去神经支配率为24%。尽管增加血管周围MnSOD免疫反应，有营养不良ACh静脉曲张或其加重损失的血管周围地区没有证据。此外，几乎没有迹象表明酪氨酸硝化ChAT神经末梢或神经元细胞体。这些数据表明，聚集AP发挥早期，非选择性和局灶性神经毒性作用的ACh和5-HT轴突，但选择性，斑块和氧化应激独立的弥漫性胆碱毒性，最有可能引起的可溶性AP组件，负责海马和皮质ACh去神经支配。(c)2005年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Alzheimer's disease (AD) is characterized by increases in amyloid-beta (AP) peptides, neurofibrillary tangles, oxidative stress and cholinergic deficits. However, the selectivity of these deficits and their relation with the AP pathology or oxidative stress remain unclear. We therefore investigated amyloidosis-related changes in acetylcholine (ACh) and serotonin (5-HT) innervations of hippocampus and parietal cortex by quantitative choline acetyltransferase (ChAT) and 5-HT immunocytochemistry, in 6,12/14 and 18 month-old transgenic mice carrying familial AD-linked mutations (hAPP(Sw,Ind)). Further, using manganese superoxide dismutase (MnSOD) and nitrotyrosine immunoreactivity as markers, we evaluated the relationship between oxidative stress and the ACh deficit in 18 month-old mice. Thioflavin-positive AP plaques were seen in both regions at all ages; they were more numerous in hippocampus and increased in number (> 15-fold) and size as a function of age. A majority of plaques exhibited or were surrounded by increased MnSOD immunoreactivity, and dystrophic ACh or 5-HT axons were seen in their immediate vicinity. Counts of immunoreactive axon varicosities revealed significant decreases in ACh innervation, with a sparing of the 5-HT, even in aged mice. First apparent in hippocampus, the loss of ACh terminals was in the order of 20% at 12/14 months, and not significantly greater (26%) at 18 months. In parietal cortex, the ACh denervation was significant at 18 months only, averaging 24% across the different layers. Despite increased perivascular MnSOD immunoreactivity, there was no evidence of dystrophic ACh varicosities or their accentuated loss in the perivascular area. Moreover, there was virtually no sign of tyrosine nitration in ChAT nerve terminals or neuronal cell bodies. These data suggest that aggregated AP exerts an early, non-selective and focal neurotoxic effect on both ACh and 5-HT axons, but that a selective, plaque- and oxidative stress-independent diffuse cholinotoxicity, most likely caused by soluble AP assemblies, is responsible for the hippocampal and cortical ACh denervation. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.