Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function.
Apoε4 disrupts neurovascular regulation and undermines white matter integrity and cognitive function.
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DOI：
10.1038/s41467-018-06301-2
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发表时间：
2018-09-19
影响因子：
16.6
通讯作者：
Iadecola C
中科院分区：
文献类型：
--
作者：
Koizumi K;Hattori Y;Ahn SJ;Buendia I;Ciacciarelli A;Uekawa K;Wang G;Hiller A;Zhao L;Voss HU;Paul SM;Schaffer C;Park L;Iadecola C
ApoE4等位基因与小血管疾病风险增加相关，小血管疾病是血管认知障碍的原因之一。在这里，我们报告了用人ApoE4靶向替换ApoE基因的小鼠与ApoE3-tr小鼠相比，新皮质血流量减少了，这是由于降低了血管密度而不是减缓了微血管红细胞流动。此外，在ApoE4-tr小鼠中，匹配局部血流输送和脑活动的动态平衡机制受到损害。在大脑低灌流的模型中，这些脑血管变化加剧了对胼胝体白质的损害，并加剧了认知功能障碍。使用3光子显微镜，我们发现白质损伤的增加与微血管血流的增强减少有关，导致局部缺氧。这种改变可能是携带ApoE4等位基因的人皮质下白质对缺氧缺血性损害的易感性增加的原因。载脂蛋白E4是小血管疾病的危险因素，可导致认知障碍。在这里，作者使用3光子显微镜评估了胼胝体的微血管结构，发现表达ApoE4等位基因的小鼠比野生型更容易受到脑白质损伤和认知障碍的影响，在低灌流诱导的缺氧模型中。
The ApoE4 allele is associated with increased risk of small vessel disease, which is a cause of vascular cognitive impairment. Here, we report that mice with targeted replacement (TR) of the ApoE gene with human ApoE4 have reduced neocortical cerebral blood flow compared to ApoE3-TR mice, an effect due to reduced vascular density rather than slowing of microvascular red blood cell flow. Furthermore, homeostatic mechanisms matching local delivery of blood flow to brain activity are impaired in ApoE4-TR mice. In a model of cerebral hypoperfusion, these cerebrovascular alterations exacerbate damage to the white matter of the corpus callosum and worsen cognitive dysfunction. Using 3-photon microscopy we found that the increased white matter damage is linked to an enhanced reduction of microvascular flow resulting in local hypoxia. Such alterations may be responsible for the increased susceptibility to hypoxic-ischemic lesions in the subcortical white matter of individuals carrying the ApoE4 allele. ApoE4 is a risk factor for small vessel disease, which can lead to cognitive impairment. Here the authors assess the microvasculature of the corpus callosum using 3-photon microscopy and find that mice expressing the ApoE4 allele are more susceptible than wild-type to white matter injury and cognitive impairment in a model of hypoperfusion-induced hypoxia.
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影响因子：
14.8
作者：
Holtmaat, Anthony;Bonhoeffer, Tobias;Chow, David K.;Chuckowree, Jyoti;De Paola, Vincenzo;Hofer, Sonja B.;Huebener, Mark;Keck, Tara;Knott, Graham;Lee, Wei-Chung A.;Mostany, Ricardo;Mrsic-Flogel, Tom D.;Nedivi, Elly;Portera-Cailliau, Carlos;Svoboda, Karel;Trachtenberg, Joshua T.;Wilbrecht, Linda
通讯作者：
Wilbrecht, Linda
DOI：
10.1523/jneurosci.3367-10.2010
发表时间：
2010-09-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Coleman CG;Wang G;Park L;Anrather J;Delagrammatikas GJ;Chan J;Zhou J;Iadecola C;Pickel VM
通讯作者：
Pickel VM
影响因子：
3.6
作者：
Jofre-Monseny, Laia;de Pascual-Teresa, Sonia;Rimbach, Gerald
通讯作者：
Rimbach, Gerald
影响因子：
3.4
作者：
Farrar, Matthew J.;Wise, Frank W.;Schaffer, Chris B.
通讯作者：
Schaffer, Chris B.
血管认知障碍的翻译模型：包括较大物种的综述。
影响因子：
9.3
作者：
Hainsworth AH;Allan SM;Boltze J;Cunningham C;Farris C;Head E;Ihara M;Isaacs JD;Kalaria RN;Lesnik Oberstein SA;Moss MB;Nitzsche B;Rosenberg GA;Rutten JW;Salkovic-Petrisic M;Troen AM
通讯作者：
Troen AM