Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease
Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease
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DOI：
10.2174/156720507780362245
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发表时间：
2007-04-01
影响因子：
2.1
通讯作者：
Zlokovic, Berislav V.
中科院分区：
文献类型：
--
作者：
Deane, Rashid;Zlokovic, Berislav V.
脑血管功能障碍有助于阿尔茨海默病（AD）的认知能力下降和痴呆，并且可能先于脑淀粉样血管病和阿尔茨海默病神经毒素淀粉样β肽（AP）的脑积聚。血脑屏障（BBB）对脑A β稳态至关重要，并通过两个主要受体，低密度脂蛋白受体相关蛋白1 （LR-P1）和晚期糖基化终产物受体（RAGE）调节AP运输。根据AD的神经血管假说，通过LRP1/ rage介导的转运失调、血管生成异常和动脉功能障碍导致的A β血脑屏障清除错误可能引发神经血管解偶联、AP积累、脑血管退化、脑灌注不足和神经血管炎症。最终，这些事件导致血脑屏障受损和神经元“环境”中的化学失衡，并导致突触和神经元功能障碍。基于神经血管假说，我们提出了一系列新的潜在治疗方法，可以减少神经炎症，增强AP清除和神经血管修复，并改善脑血流量。基于rage和基于lrp1的治疗策略有可能控制AD患者的脑AP，以及可能相关的家族性脑血管p -淀粉样变性。此外，我们还发现了两个血管限制性基因，即控制LRP1在脑毛细血管和脑血管生成中的表达的GAX（生长停滞特异性同源盒）和控制脑动脉平滑肌细胞收缩性并影响脑血流的心肌素（心肌素）。这些发现为阿尔茨海默病血管功能障碍的新致病途径提供了见解，并指出了阿尔茨海默病的新治疗靶点。
Cerebrovascular dysfunction contributes to the cognitive decline and dementia in Alzheimer's disease (AD), and may precede cerebral amyloid angiopathy and brain accumulation of the Alzheimer's neurotoxin, amyloid beta-peptide (AP). The blood-brain barrier (BBB) is critical for brain A beta homeostasis and regulates AP transport via two main receptors, the low density lipoprotein receptor related protein 1 (LR-P1) and the receptor for advanced glycation end products (RAGE). According to the neurovascular hypothesis of AD, faulty BBB clearance of A beta through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, AP accumulation, cerebrovascular regression, brain hypoperfusion and neurovascular inflammation. Ultimately these events lead to BBB compromise and chemical imbalance in the neuronal 'milieu', and result in synaptic and neuronal dysfunction. Based on the neurovascular hypothesis, we suggest an array of new potential therapeutic approaches that could be developed for AD to reduce neuroinflammation, enhance AP clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain AP in AD, and possibly related familial cerebrovascular P-amyloidoses. In addition, we have identified two vascularly restricted genes, GAX (growth arrest-specific homeobox), which controls LRP1 expression in brain capillaries and brain angiogenesis, and MYOCD (myocardin), which controls contractility of cerebral arterial smooth muscle cells and influences cerebral blood flow. These findings provide insights into new pathogenic pathways for the vascular dysfunction in AD and point to new therapeutic targets for AD.