Deane Rashid, Zlokovic Berislav V
Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
Curr Alzheimer Res. 2007 Apr;4(2):191-7. doi: 10.2174/156720507780362245.
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 (Abeta). The blood-brain barrier (BBB) is critical for brain Abeta homeostasis and regulates Abeta transport via two main receptors, the low density lipoprotein receptor related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE). According to the neurovascular hypothesis of AD, faulty BBB clearance of Abeta through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, Abeta 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 Abeta clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain Abeta in AD, and possibly related familial cerebrovascular beta-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.
脑血管功能障碍会导致阿尔茨海默病（AD）患者认知能力下降和痴呆，并且可能先于脑淀粉样血管病以及阿尔茨海默病神经毒素β淀粉样肽（Aβ）在大脑中的积累出现。血脑屏障（BBB）对于大脑Aβ稳态至关重要，并通过两种主要受体，即低密度脂蛋白受体相关蛋白1（LRP1）和晚期糖基化终产物受体（RAGE）来调节Aβ转运。根据AD的神经血管假说，通过LRP1/RAGE介导的转运失调、异常血管生成和动脉功能障碍导致的Aβ血脑屏障清除缺陷，可能引发神经血管解偶联、Aβ积累、脑血管退化、脑灌注不足和神经血管炎症。最终，这些事件会导致血脑屏障受损以及神经元“微环境”中的化学失衡，进而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，可用于AD的治疗，以减轻神经炎症、增强Aβ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患者大脑中的Aβ，以及可能相关的家族性脑血管β淀粉样变性。此外，我们还确定了两个血管特异性基因，即GAX（生长停滞特异性同源盒基因），它控制脑毛细血管中LRP1的表达和脑血管生成；以及MYOCD（心肌转录因子），它控制脑动脉平滑肌细胞的收缩性并影响脑血流量。这些发现为AD血管功能障碍的新致病途径提供了见解，并指出了AD的新治疗靶点。
