Modeling Mixed Vascular and Alzheimer's Dementia Using Focal Subcortical Ischemic Stroke in Human ApoE4-TR:5XFAD Transgenic Mice.
Modeling Mixed Vascular and Alzheimer's Dementia Using Focal Subcortical Ischemic Stroke in Human ApoE4-TR:5XFAD Transgenic Mice.
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DOI：
10.1007/s12975-020-00786-0
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发表时间：
2020-10
影响因子：
6.9
通讯作者：
Hinman, Jason D.
中科院分区：
文献类型：
--
作者：
Hayden, Eric Y.;Huang, Julia M.;Charreton, Malena;Nunez, Stefanie M.;Putman, Jennifer N.;Teter, Bruce;Lee, Jason T.;Welch, Andrew;Frautschy, Sally;Cole, Gregory;Teng, Edmond;Hinman, Jason D.
皮质下白质缺血性病变在阿尔茨海默病（AD）患者中被越来越多地认识到存在病理重叠。AD中所见的白质缺血性病变与淀粉样蛋白病理的相互作用尚未得到充分阐明。我们设计了一种新的皮质下白质缺血性脑卒中和AD小鼠模型，它可以增进我们对混合性血管性痴呆和AD痴呆的细胞和分子机制的理解。通过局部立体定向注射一种不可逆的内皮型一氧化氮合酶（eNOS）抑制剂，诱导前肢运动皮层下方的皮质下白质缺血性脑卒中。在8周龄的人载脂蛋白E4靶向替代（TR）：5XFAD小鼠上进行皮质下白质缺血性脑卒中和假手术操作。在7、10、15和20周进行行为测试。一部分动物接受了18氟 - 脱氧葡萄糖正电子发射断层扫描/计算机断层扫描（18FDG - PET/CT）。在20周龄时，检查脑组织的淀粉样斑块积累和细胞变化。与假手术的E4 - TR：5XFAD小鼠相比，早期发生皮质下缺血性脑卒中的小鼠在皮质下脑卒中上方的皮质区域淀粉样斑块负荷显著降低。与假手术的E4 - TR：5XFAD动物相比，发生脑卒中的E4 - TR：5XFAD小鼠认知能力有所提高。与假手术的E4 - TR：5XFAD小鼠相比，皮质下脑卒中上方皮质区域的Iba - 1阳性小胶质细胞数量和形态复杂性增加，这表明在皮质下脑卒中后，活化的小胶质细胞与皮质神经元之间的相互作用可能促进了淀粉样蛋白的清除。这种模拟混合性血管性痴呆和AD痴呆的新方法为剖析这两种常见病理之间的分子相互作用提供了一个有价值的工具。
Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer’s disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8 weeks of age. Behavioral tests were done at 7, 10, 15, and 20 weeks. A subset of animals underwent 18FDG-PET/CT. At 20 weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.
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影响因子：
8.8
作者：
Mathys H;Adaikkan C;Gao F;Young JZ;Manet E;Hemberg M;De Jager PL;Ransohoff RM;Regev A;Tsai LH
通讯作者：
Tsai LH
影响因子：
19.7
作者：
Prescott, Jeffrey W.;Guidon, Arnaud;Petrella, Jeffrey R.
通讯作者：
Petrella, Jeffrey R.
DOI：
10.1056/nejmoa1204133
发表时间：
2012-08-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
SPS3 Investigators;Benavente OR;Hart RG;McClure LA;Szychowski JM;Coffey CS;Pearce LA
通讯作者：
Pearce LA
影响因子：
4.8
作者：
Hinman JD
通讯作者：
Hinman JD
影响因子：
11.2
作者：
Lee S;Viqar F;Zimmerman ME;Narkhede A;Tosto G;Benzinger TL;Marcus DS;Fagan AM;Goate A;Fox NC;Cairns NJ;Holtzman DM;Buckles V;Ghetti B;McDade E;Martins RN;Saykin AJ;Masters CL;Ringman JM;Ryan NS;Förster S;Laske C;Schofield PR;Sperling RA;Salloway S;Correia S;Jack C Jr;Weiner M;Bateman RJ;Morris JC;Mayeux R;Brickman AM;Dominantly Inherited Alzheimer Network
通讯作者：
Dominantly Inherited Alzheimer Network