Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.
Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.
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DOI：
10.1161/hypertensionaha.112.195511
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发表时间：
2012-07
期刊：
影响因子：
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通讯作者：
Lembo G
中科院分区：
文献类型：
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作者：
Carnevale D;Mascio G;D'Andrea I;Fardella V;Bell RD;Branchi I;Pallante F;Zlokovic B;Yan SS;Lembo G
尽管流行病学数据表明高血压与患阿尔茨海默病的强烈倾向相关，但到目前为止尚无机制上的解释。我们建立了一种通过横向主动脉缩窄获得的高血压模型，该模型导致了阿尔茨海默病的典型病变，如淀粉样斑块、神经炎症、血脑屏障功能障碍和认知障碍，这些在此首次展示。这项工作的目的是研究高血压小鼠阿尔茨海默病所涉及的机制。我们聚焦于晚期糖基化终末产物受体（RAGE），它在血脑屏障处对β - 淀粉样蛋白（Aβ）的转运起关键调节作用，并且可能受到血管因素的影响。
高血压刺激对大脑皮质和海马血管中的RAGE上调具有早期且持续的作用。有趣的是，抑制RAGE可防止高血压诱导的阿尔茨海默病病理改变，这从认知障碍和脑实质Aβ沉积的改善中得以体现。在横向主动脉缩窄（TAC）小鼠中，RAGE表达增加是由循环中晚期糖基化终末产物（AGEs）增加所诱导，并因它们后来在脑血管中的沉积而持续。有趣的是，每日使用一种AGEs抑制剂或抗氧化剂进行治疗可阻止阿尔茨海默病特征的发展。
到目前为止，在实验动物模型中阿尔茨海默病病理仅在过表达淀粉样前体的转基因小鼠中得到确认。这是第一项表明慢性血管损伤可激活脑血管RAGE，促进脑实质Aβ沉积和认知恶化发生的研究。
总体而言，我们证明脑血管中的RAGE激活是高血压诱导的阿尔茨海默病中的一个关键致病事件，这表明抑制该靶点可限制血管相关阿尔茨海默病的发生。
Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer’s Disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by Transverse Aortic Constriction, leading to alterations typical of Alzheimer’s Disease, such as amyloid plaques, neuroinflammation, Blood Brain Barrier dysfunction and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer’s Disease of hypertensive mice. We focused on RAGE, that critically regulates Aβ transport at the Blood Brain Barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE up-regulation in brain vessels of cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in TAC mice was induced by increased circulating AGEs and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an AGEs inhibitor or antioxidant prevented the development of Alzheimer’s traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer’s Disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer.