Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating β/γ-Secretases
Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating β/γ-Secretases
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DOI：
10.1007/s11064-017-2391-9
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发表时间：
2017-12-01
影响因子：
4.4
通讯作者：
Tian, Fuming
中科院分区：
文献类型：
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作者：
Cai, Zhiyou;Liu, Zhou;Tian, Fuming
慢性脑灌注不足（CCH）与阿尔茨海默病样发病机制有关，但 CCH 与阿尔茨海默病（AD）发生之间的关系仍不清楚。目的是阐明 CCH 诱导的淀粉样蛋白-β (A beta) 病理学领域的潜在病理生理学机制。已开发出一种具有双侧颈总动脉永久闭塞 (BCCAO) 的 CCH 大鼠模型。采用Morris水迷宫测试大鼠的认知功能。通过酶联免疫吸附测定测定Aβ（Aβ40和Aβ42）和可溶性淀粉样前体蛋白（sAPP：sAPPα和sAPPβ）的水平。采用Western blotting检测β位点淀粉样蛋白前体蛋白裂解酶1（BACE1）、早老素1（PS1）、尼卡斯特林（NCT）、前咽缺陷1α（Aph-1α）和早老素增强子2（Pen-2）、sAPPα和sAPPβ的表达。莫里斯水迷宫试验表明，CCH 会导致与海马 Aβ 水平相关的学习和记忆能力下降。 CCH大鼠海马sAPP α、ADAM10、ADAM17水平均高于对照组（P < 0.05）； sAPP beta、BACE 和 BACE1 水平较对照组升高幅度更大（P < 0.05）。 CCH干预（1周或4周）显着增加大鼠海马PS1、Aph-1α和Pen-2的表达，但对NCT没有影响。 CCH 会导致认知障碍，并通过分别提高 β 分泌酶/γ 分泌酶和 α 分泌酶的活性来改变 APP 加工的淀粉样蛋白生成和非淀粉样蛋白生成途径。非淀粉样蛋白生成途径不能克服淀粉样蛋白生成途径在慢性脑低灌注过程中的损伤作用，促进β-淀粉样蛋白发病。
Chronic cerebral hypoperfusion (CCH) contributes to the Alzheimer's-like pathogenesis, but the relationship between CCH and the occurrence of Alzheimer's disease (AD) remains obscure. The aim is to elucidate the potential pathophysiological mechanism in the field of amyloid-beta (A beta) pathology induced by CCH. A rat model of CCH has been developed with permanent bilateral occlusion of common carotid arteries (BCCAO). The cognitive function of rats was tested by the Morris water maze. The levels of A beta (A beta 40 and A beta 42) and soluble amyloid precursor protein (sAPP: sAPP alpha and sAPP beta) were determined by enzyme linked immunosorbent assay. The expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), presenilin1 (PS1), nicastrin (NCT), anterior pharynx-defective 1alpha (Aph-1 alpha) and presenilin enhancer 2 (Pen-2), sAPP alpha and sAPP beta were detected by Western blotting. Morris water maze test showed that CCH induced decline in learning and memory related to A beta levels in the hippocampus. The levels of sAPP alpha, ADAM10 and ADAM17 in the hippocampus of CCH rats were higher than the control ones (P < 0.05); the levels of sAPP beta, BACE and BACE1 increased more than the control ones (P < 0.05). CCH intervention (1-week or 4-week) markedly increased the expression of PS1, Aph-1 alpha and Pen-2 in the hippocampus of rats, but had no effect on NCT. CCH contributed to cognitive impairment and altered the amyloidogenic and non-amyloidogenic pathway of APP processing by boosting the activity of beta-secretase/gamma-secretase and alpha-secretase respectively. The non-amyloidogenic pathway can't overcome the damage role of the amyloidogenic pathway in the process of chronic cerebral hypoperfusion which promotes amyloid-beta pathogenesis.