Mouse models of Alzheimer's disease cause rarefaction of pial collaterals and increased severity of ischemic stroke.
Mouse models of Alzheimer's disease cause rarefaction of pial collaterals and increased severity of ischemic stroke.
复制标题
阿尔茨海默病小鼠模型会导致软脑膜络脉稀疏并增加缺血性中风的严重程度。
DOI：
10.1007/s10456-018-9655-0
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发表时间：
2019
期刊：
影响因子：
9.8
通讯作者：
Faber,JamesE
中科院分区：
文献类型：
--
作者：
Zhang,Hua;Jin,Bo;Faber,JamesE
血管功能障碍有助于阿尔茨海默病（AD）的进展和严重程度。阿尔茨海默病患者在缺血性脑卒中后也存在较大的梗死；然而，其机制尚不清楚。脑卒中的主要保护来源是脊髓侧索。不幸的是，自然衰老和其他血管危险因素导致侧支数量和直径的减少（稀疏）和中风严重程度的增加。在此，我们验证了AD加速年龄诱导的侧支稀疏的假设，并研究了潜在的潜在机制。三倍和双倍转基因AD小鼠模型在8月龄时均能维持侧支细胞的稀薄，远远早于单独衰老引起的稀薄（16月龄）。在18个月大时没有进一步进展的梗死灶缩小伴随着MCA闭塞后梗死体积增加两倍。AD不诱导类似大小的动脉小动脉或穿透性小动脉的稀疏。在阿尔茨海默病的实质血管淀粉样蛋白模型中，极少发生，仅在18个月大时发生。稀释度与侧支或顶动脉的淀粉样蛋白沉积无关，侧支带下的斑块负担或CD11b+细胞密度也不高于其他部位。然而，稀薄伴随着氧化应激、炎症和侧枝内皮细胞和壁细胞衰老标志物的增加。此外，CX3CR1的缺失减少了细胞的稀疏性，eNOS的过表达阻止了细胞的稀疏性。这些发现表明，AD小鼠模型促进了侧支细胞的稀疏，并暗示炎症诱导的侧支壁细胞加速衰老。减少血管炎症和/或增加一氧化氮的策略可以保护侧枝功能。
Vascular dysfunction contributes to the progression and severity of Alzheimer’s disease (AD). Patients with AD also sustain larger infarctions after ischemic stroke; however, the responsible mechanisms are unknown. Pial collaterals are the primary source of protection in stroke. Unfortunately, natural aging and other vascular risk factors cause a decline in collateral number and diameter (rarefaction) and an increase in stroke severity. Herein, we tested the hypothesis that AD accelerates age-induced collateral rarefaction and examined potential underlying mechanisms. Triple and double transgenic mouse models of AD both sustained collateral rarefaction by 8 months of age, well before the onset of rarefaction caused by aging alone (16 months of age). Rarefaction, which did not progress further at 18 months of age, was accompanied by a twofold increase in infarct volume after MCA occlusion. AD did not induce rarefaction of similarly sized pial arterioles or penetrating arterioles. Rarefaction was minimal and occurred only at 18 months of age in a parenchymal vascular amyloid-beta model of AD. Rarefaction was not associated with amyloid-beta deposition on collaterals or pial arteries, nor was plaque burden or CD11b+cell density greater in brain underlying the collateral zones versus elsewhere. However, rarefaction was accompanied by increased markers of oxidative stress, inflammation, and aging of collateral endothelial and mural cells. Moreover, rarefaction was lessened by deletion of CX3CR1 and prevented by overexpression of eNOS. These findings demonstrate that mouse models of AD promote rarefaction of pial collaterals and implicate inflammation-induced accelerated aging of collateral wall cells. Strategies that reduce vascular inflammation and/or increase nitric oxide may preserve collateral function.