School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
Brain Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China.
Mol Neurobiol. 2020 Jan;57(1):278-289. doi: 10.1007/s12035-019-01697-4. Epub 2019 Jul 19.
Cerebral amyloid angiopathy (CAA) refers to pathological changes occurring in cerebral blood vessels caused by deposition of beta amyloid (Aβ) protein. However, the mechanisms involved in the origin of Aβ for the formation of CAA and its link to parenchymal amyloid depositions remained to be unraveled. Here, we found CAA and parenchymal plaques distributed separately instead of mingling with each other in the spinal cord of TgCRND8 mice. Parenchymal plaques predominantly located in the dorsal horn whereas CAA distributed in the ventral horn. We further found that the ratio of Aβ40/Aβ42 was significantly higher in the ventral than that in the dorsal by ELISA assay, suggesting that origin of Aβ forming parenchymal plaques may be different from that of CAA in the spinal cord. This hypothesis was further demonstrated by the surgical methods which indicated eliminating parenchymal plaques did not alter CAA in the affected spinal cord. We also examined the ratio of Aβ40/Aβ42 in the cerebral spinal fluid (CSF) in order to identify the origin of the CAA formation, and found the Aβ40/Aβ42 ratio was similar to that of CAA formation in the ventral horn. We further demonstrated that CSF tracer distributed along ventral horn vessels, in exactly the same pattern as Aβ deposition in CAA in ventral part of spinal cord. These findings verified the concept that CSF influx may act as a constant source for delivering Aβ, and contribute to the growth of paraarterial deposits in CAA. Taken together, the results of the present study highlight the important role of the Aβ40/Aβ42 ratio in determining vascular versus parenchymal amyloid deposition. Unlike parenchymal plaques, Aβ of CAA comes from CSF; thus, manipulation of CSF Aβ could represent a novel strategy to treat CAA.
脑淀粉样血管病（Cerebral amyloid angiopathy，CAA）是指β淀粉样蛋白（β amyloid，Aβ）沉积引起的脑血管病变。然而，Aβ起源与 CAA 形成的机制及其与实质淀粉样沉积的关系仍有待阐明。在这里，我们发现 TgCRND8 小鼠脊髓中的 CAA 和实质斑块是分别分布的，而不是相互混合的。实质斑块主要位于背角，而 CAA 则分布在腹角。我们进一步发现，ELISA 检测显示，腹角 Aβ40/Aβ42 的比值明显高于背角，提示形成实质斑块的 Aβ 起源可能与脊髓中的 CAA 不同。这一假设通过手术方法进一步得到证实，即消除实质斑块不会改变受影响脊髓中的 CAA。我们还检查了脑脊髓液（CSF）中的 Aβ40/Aβ42 比值，以确定 CAA 形成的起源，发现 Aβ40/Aβ42 比值与腹角 CAA 形成相似。我们进一步证明，CSF 示踪剂沿腹角血管分布，与脊髓腹侧 CAA 中 Aβ 沉积的分布完全一致。这些发现验证了 CSF 内流可能作为 Aβ 的恒定来源，促进 CAA 中血管周围沉积增长的概念。总之，本研究的结果强调了 Aβ40/Aβ42 比值在决定血管与实质淀粉样沉积中的重要作用。与实质斑块不同，CAA 的 Aβ 来自 CSF；因此，CSF Aβ 的操作可能代表一种治疗 CAA 的新策略。
