Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A.
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DOI：
10.1038/nature11087
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发表时间：
2012-05-16
期刊：
影响因子：
64.8
通讯作者：
Zlokovic, Berislav V.
中科院分区：
文献类型：
--
作者：
Bell, Robert D.;Winkler, Ethan A.;Singh, Itender;Sagare, Abhay P.;Deane, Rashid;Wu, Zhenhua;Holtzman, David M.;Betsholtz, Christer;Armulik, Annika;Sallstrom, Jan;Berk, Bradford C.;Zlokovic, Berislav V.
人载脂蛋白E有三种亚型：APOE 2、APOE 3和APOE 4。APOE 4是阿尔茨海默病的主要遗传风险因素，与唐氏综合征痴呆和创伤性脑损伤和出血后神经功能不良有关。神经血管功能障碍存在于正常APOE 4携带者和APOE 4相关疾病个体中。在小鼠中，缺乏Apoe导致血脑屏障（BBB）破坏，而APOE 4增加BBB对损伤的易感性。载脂蛋白E基因型如何影响脑微循环仍然是一个谜。使用不同的APOE转基因小鼠，包括切除和/或抑制亲环蛋白A（CypA）的小鼠，我们发现APOE 4的表达和小鼠Apoe的缺乏，而不是APOE 2和APOE 3，通过激活周细胞中的促炎性CypA-核因子-κ B-基质金属蛋白酶-9途径导致BBB破坏。这反过来又导致神经元摄取多种血液来源的神经毒性蛋白，以及微血管和脑血流量减少。我们发现ApoE缺陷和APOE 4表达小鼠的血管缺陷先于神经元功能障碍，并可引发神经退行性变化。星形胶质细胞分泌的APOE 3，而不是APOE 4，通过脂蛋白受体抑制周细胞中的CypA-核因子-κ B-基质金属蛋白酶-9通路。我们的数据表明，CypA是治疗APOE 4介导的神经血管损伤和由此产生的神经元功能障碍和变性的关键靶点。
Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer’s disease and is associated with Down’s syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals withAPOE4-associated disorders. In mice, lack of Apoe leads to blood–brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
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影响因子：
16.2
作者：
Kim, Jungsu;Basak, Jacob M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
8.3
作者：
Candelario-Jalil E;Thompson J;Taheri S;Grossetete M;Adair JC;Edmonds E;Prestopnik J;Wills J;Rosenberg GA
通讯作者：
Rosenberg GA
影响因子：
--
作者：
Thambisetty, Madhav;Beason-Held, Lori;An, Yang;Kraut, Michael A.;Resnick, Susan M.
通讯作者：
Resnick, Susan M.
DOI：
10.1001/jama.1997.03540340047031
发表时间：
1997-03-12
影响因子：
120.7
作者：
Snowdon, DA;Greiner, LH;Markesbery, WR
通讯作者：
Markesbery, WR
影响因子：
4.2
作者：
Zipser, B. D.;Johanson, C. E.;Stopa, E. G.
通讯作者：
Stopa, E. G.