Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice
Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice
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DOI：
10.1016/j.brainres.2009.07.078
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发表时间：
2009-10-06
期刊：
影响因子：
2.9
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
--
作者：
Kitaguchi, Hiroshi;Tomimoto, Hidekazu;Takahashi, Ryosuke
慢性脑缺血可能加速阿尔茨海默病的临床病理改变。我们研究了慢性脑灌注不足是否会加速淀粉样蛋白前体转基因（APP-Tg）小鼠的淀粉样蛋白沉积。在5、8和11月龄时，过量表达瑞典（K670N/M671L）和印第安纳（V717F）突变的人类APP突变形式（APPSwInd）的C57Bl/6J雄性小鼠及其窝鼠同伴使用内径0.18 mm的微线圈进行假手术或双侧颈动脉狭窄（BCAS）（短周期组）。假手术或BCAS 1个月后，对这些动物进行免疫组化检测胶质纤维酸性蛋白、β淀粉样蛋白（1-40）（A β(1-40)）、β淀粉样蛋白（1-42）（A β(1-42)），以及A β的免疫印迹和过滤试验。另一批APPSwInd小鼠在3个月时进行假手术或BCAS，存活9个月后进行同样的检查（长周期组）。bcas治疗组脑白质稀薄，星形胶质细胞增生。淀粉样蛋白β(1-40)免疫反应性出现在白质的少数轴突中，而a - β(1-42)在6月龄及之后的短、长周期组分散的皮质神经元和轴突中积累。在9个月和12个月的假手术和bcas处理小鼠的神经pil中，A β(1-40)和A β(1-42)均沉积。短周期组和长周期组在12个月大时没有差异。过滤试验显示细胞外富集部分A - β原纤维增加。综上所述，慢性脑灌注不足增加了A β原纤维并诱导了A β在细胞内的沉积，因此可能加速了阿尔茨海默病的病理改变。(C) 2009 Elsevier B.V.版权所有
Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid beta deposition in amyloid protein precursor transgenic (APP-Tg) mouse. At 5, 8, and 11 months of age, C57Bl/6J male mice overexpressing a mutant form of the human APP bearing the both Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd) and their litterrmates were subjected to either sham operation or bilateral carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm (short-period group). One month after the sham operation or BCAS, these animals were examined by immunohistochemistry for glial fibrillary acidic protein, amyloid beta(1-40) (A beta(1-40)), amyloid beta(1-42) (A beta(1-42)), as well as Western blotting and filter assay for A beta. Another batch of the littermates of APPSwInd mice were subjected to either sham operation or BCAS at 3 months and were examined in the same manner after survival for 9 months (long-period group). in the BCAS-treated group, the white matter was rarefied and astroglia was proliferated. Amyloid beta(1-40) immunoreactivity was found in a few axons in the white matter after BCAS, whereas A beta(1-42) was accumulated in the scattered cortical neurons and the axons at ages of 6 months and thereafter in the short- and long-period groups. In the neuropil, both A beta(1-40) and A beta(1-42) were deposited in the sham-operated and BCAS-treated mice at ages of 9 and 12 months. There were no differences between the short-period group at ages of 12 months and the long-period group. Filter assay showed an increase of A beta fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased A beta fibrils and induced A beta deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease. (C) 2009 Elsevier B.V. All rights reserved.