Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation.
Mild chronic cerebral hypoperfusion induces neurovascular dysfunction, triggering peripheral beta-amyloid brain entry and aggregation.
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DOI：
10.1186/2051-5960-1-75
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发表时间：
2013-11-13
影响因子：
7.1
通讯作者：
Rivest S
中科院分区：
文献类型：
--
作者：
ElAli A;Thériault P;Préfontaine P;Rivest S
血脑屏障（BBB）控制大脑的氧气和营养供应，并保护大脑免受有毒代谢物，如β -淀粉样蛋白（Aβ）肽。神经血管单元（NVU）通过根据大脑需要控制血脑屏障参数，将血管和神经元功能结合起来。因此，NVU/BBB功能障碍与脑血流（CBF）异常相关，已被提出主要通过损害大脑Aβ清除参与阿尔茨海默病（AD）的发病机制。然而，NVU/BBB在神经退行性级联中的时空贡献仍然难以捉摸。通过右颈总动脉（rCCA）永久性结扎C57BL/6J小鼠以诱导轻度慢性脑灌注不足，我们发现脑灌注不足通过降低脑毛细血管中ABCB1蛋白的表达来诱导NVU功能障碍。ABCB1的减少主要是由糖原合成酶激酶3 （GSK3β）激活增强引起的，这降低了β-连环蛋白的核丰度。此外，大脑低灌注触发了周围应用的人Aβ1-42肽的早期血管沉积，6周后从高度血管转移到实质，形成小而稳定的Aβ沉积。低灌注诱导葡萄糖代谢失调，如脑再灌注，或给药高剂量葡萄糖，降低GSK3β激活，恢复β-catenin核丰富度，重建ABCB1蛋白表达，并阻止a β血管早期沉积。这些结果表明，轻度慢性脑灌注不足会产生代谢失调的微环境，从而触发外周应用的人a - β1-42肽进入大脑并聚集。我们的研究为阿尔茨海默病中观察到的神经退行性级联反应的开始提供了新的见解，这可能对制定适当的治疗策略有价值。
The Blood–brain barrier (BBB) controls brain supply with oxygen and nutrients, and protects the brain from toxic metabolites, such as beta-amyloid (Aβ) peptides. The neurovascular unit (NVU) couples vascular and neuronal functions by controlling BBB parameters based on brain needs. As such, NVU/BBB dysfunction, associated to irregularities in cerebral blood flow (CBF), has been proposed to contribute in the pathogenesis of Alzheimer’s disease (AD), mainly by impairing cerebral Aβ clearance. However, the spatiotemporal contribution of the NVU/BBB in the neurodegenerative cascades remains elusive. By using C57BL/6J mice subjected to right common carotid artery (rCCA) permanent ligation in order to induce mild chronic cerebral hypoperfusion, we show here that cerebral hypoperfusion induced NVU dysfunction by reducing ABCB1 protein expression in brain capillaries. ABCB1 reduction was mainly triggered by an enhanced Glycogen Synthase Kinase 3 (GSK3β) activation, which decreased β-catenin nuclear abundance. Moreover, cerebral hypoperfusion triggered early vascular deposition of peripherally applied human Aβ1-42 peptides, which has shifted from highly vascular to the parenchyma 6 weeks later, forming small stable Aβ deposits. Hypoperfusion induced a deregulation in glucose metabolism, as brain reperfusion, or the administration of a high dose of glucose, diminished GSK3β activation, recuperated β-catenin nuclear abundance, reestablished ABCB1 protein expression, and prevented Aβ vascular early deposition. These results demonstrate that mild chronic cerebral hypoperfusion creates a metabolically deregulated microenvironment, thus triggering the brain entry and aggregation of peripherally applied human Aβ1-42 peptides. Our study offers new insights on the initiation of the neurodegenerative cascades observed in AD, which could be valuable in developing adequate treatment strategies.
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影响因子：
12.7
作者：
Arbel-Ornath M;Hudry E;Eikermann-Haerter K;Hou S;Gregory JL;Zhao L;Betensky RA;Frosch MP;Greenberg SM;Bacskai BJ
通讯作者：
Bacskai BJ
阿尔茨海默氏病的GSK3假设。
影响因子：
4.7
作者：
Hooper C;Killick R;Lovestone S
通讯作者：
Lovestone S
影响因子：
4.8
作者：
Clodfelder-Miller, B;De Sarno, P;Jope, RS
通讯作者：
Jope, RS
影响因子：
56.9
作者：
Meyer-Luehmann, Melanie;Coomaraswamy, Janaky;Jucker, Mathias
通讯作者：
Jucker, Mathias
影响因子：
4.2
作者：
Pimentel-Coelho, Pedro M.;Michaud, Jean-Philippe;Rivest, Serge
通讯作者：
Rivest, Serge