Abstract:
Although the concept that the blood-brain barrier (BBB) plays an important role in the etiology and pathogenesis of Alzheimer\'s disease (AD) has become increasingly accepted, little is known yet about how it actually contributes. We and others have recently identified a novel functionally distinct subset of BBB pericytes (PCs). In the present study, we sought to determine whether these PC subsets differentially contribute to AD-associated pathologies by immunohistochemistry and amyloid beta (Aβ) peptidomics. We demonstrated that a disease-associated PC subset (PC2) expanded in AD patients compared to age-matched, cognitively unimpaired controls. Surprisingly, we found that this increase in the percentage of PC2 (%PC2) was correlated negatively with BBB breakdown in AD patients, unlike in natural aging or other reported disease conditions. The higher %PC2 in AD patients was also correlated with a lower Aβ42 plaque load and a lower Aβ42:Aβ40 ratio in the brain as determined by immunohistochemistry. Colocalization analysis of multicolor confocal immunofluorescence microscopy images suggests that AD patient with low %PC2 have higher BBB breakdown due to internalization of Aβ42 by the physiologically normal PC subset (PC1) and their concomitant cell death leading to more vessels without PCs and increased plaque load. On the contrary, it appears that PC2 can secrete cathepsin D to cleave and degrade Aβ built up outside of PC2 into more soluble forms, ultimately contributing to less BBB breakdown and reducing Aβ plaque load. Collectively our data shows functionally distinct mechanisms for PC1 and PC2 in high Aβ conditions, demonstrating the importance of correctly identifying these populations when investigating the contribution of neurovascular dysfunction to AD pathogenesis.
摘要:
尽管血脑屏障(BBB)在阿尔茨海默病(AD)的病因和发病机制中起重要作用的概念已被越来越多的人接受。人们对它的实际贡献知之甚少。我们和其他人最近确定了一种新的功能不同的BBB周细胞(PC)子集。在本研究中,我们试图通过免疫组织化学和淀粉样蛋白β(Aβ)肽组学来确定这些PC亚群是否差异有助于AD相关病理。我们证明,与年龄匹配相比,AD患者的疾病相关PC子集(PC2)扩大,认知未受损的控制。令人惊讶的是,我们发现,在AD患者中,PC2百分比(%PC2)的增加与BBB击穿呈负相关,与自然衰老或其他报道的疾病状况不同。如通过免疫组织化学测定的,AD患者中较高的%PC2还与较低的Aβ42斑块负荷和较低的Aβ42:Aβ40比率相关。多色共聚焦免疫荧光显微镜图像的共定位分析表明,由于Aβ42被生理正常PC亚群(PC1)内化,具有低%PC2的AD患者具有更高的BBB分解,并且它们伴随的细胞死亡导致更多没有PC的血管和增加的斑块负荷。相反,似乎PC2可以分泌组织蛋白酶D,将PC2外部积累的Aβ裂解和降解成更可溶的形式,最终有助于减少BBB分解并减少Aβ斑块负荷。总的来说,我们的数据显示了PC1和PC2在高Aβ条件下的功能不同机制,证明在研究神经血管功能障碍对AD发病机制的贡献时正确识别这些人群的重要性。