Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer's disease.
Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2009.06.003
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发表时间：
2011-06
影响因子：
4.2
通讯作者：
Li, L.
中科院分区：
文献类型：
--
作者：
Liu, R-M;van Groen, T.;Katre, A.;Cao, D.;Kadisha, I.;Ballinger, C.;Wang, L.;Carroll, S. L.;Li, L.
淀粉样β-肽(A-β)在大脑中的积聚是阿尔茨海默病(AD)的一个病理特征；然而，其潜在的机制尚不清楚。在本研究中，我们发现组织型和尿激酶型纤溶酶原激活物(tPA和uPA)的生理抑制物纤溶酶原激活物抑制物1(PAI-1)在野生型和Aβ前体蛋白-早老素1(APP/PS1)转基因小鼠以及AD患者的脑中的表达随着年龄的增长而增加。最重要的是，我们发现敲除PAI-1基因显著降低了APP/PS1小鼠大脑中的Aβ负担，但对全长APP、α或βC末端片段的水平没有影响。此外，我们还发现，敲除PAI-1基因会导致tPA和纤溶酶活性的增加，并且纤溶酶活性与不溶于十二烷基硫酸钠的Aβ40和Aβ42的含量呈负相关。综上所述，这些数据表明，在衰老和AD中，PAI-1表达/活性的增加可能通过抑制纤溶酶原激活从而抑制Aβ的降解而对Aβ的积累起重要作用。
Accumulation of amyloid beta peptide (Aβ) in the brain is a pathological hallmark of Alzheimer’s disease (AD); the underlying mechanism, however, is not well understood. In this study, we show that expression of plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), increases with age in the brain of wild type and Aβ precursor protein-presenilin 1 (APP/PS1) transgenic mice as well as in AD patients. Most importantly, we show that knocking out the PAI-1 gene dramatically reduces Aβ burden in the brain of APP/PS1 mice but has no effect on the levels of full-length APP, alpha or beta C-terminal fragments. Furthermore, we show that knocking out the PAI-1 gene leads to increases in the activities of tPA and plasmin, and the plasmin activity inversely correlates with the amounts of SDS insoluble Aβ40 and Aβ42. Together, these data suggest that increased PAI-1 expression/activity contributes importantly to Aβ accumulation during aging and in AD probably by inhibiting plasminogen activation and thus Aβ degradation.
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影响因子：
4.2
作者：
Inestrosa, NC;Reyes, AE;Aboitiz, F
通讯作者：
Aboitiz, F
影响因子：
7.5
作者：
HASHIMOTO, Y;KOBAYASHI, A;TAKADA, A
通讯作者：
TAKADA, A
影响因子：
25
作者：
Chapman, PF;White, GL;Hsiao, KK
通讯作者：
Hsiao, KK
影响因子：
16.2
作者：
BRAMBLETT, GT;GOEDERT, M;LEE, VMY
通讯作者：
LEE, VMY
DOI：
10.1073/pnas.0230450100
发表时间：
2003-04-01
影响因子：
11.1
作者：
Farris, W;Mansourian, S;Guénette, S
通讯作者：
Guénette, S