Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 197, Road Ruijin Second, Shanghai, 200025, People's Republic of China.
BMC Neurosci. 2018 Jan 25;19(1):2. doi: 10.1186/s12868-018-0402-7.
Alzheimer's disease (AD) is characterized by the deposition of amyloid-β (Aβ) in brain parenchyma and cerebral blood vessels as cerebral amyloid angiopathy (CAA). Clusterin, a chaperon protein associated with Aβ aggregation, toxicity and transport through blood-brain barrier, may play a key role in the development of AD. Recently, clusterin peptide D-[113-122] was shown to mimic clusterin's function and exerted therapeutic effect in atherosclerosis. In this study, we investigated whether this clusterin peptide also affected (Aβ) deposition in AD transgenic mouse.
Using a micropump, synthetic peptide 113-122 of clusterin protein (20 μg/200 μl) was infused into the lateral ventricle of 8-month 5 × FAD transgenic mouse model (Tg6799), for 2 weeks. Water-maze testing showed an improved cognitive function of the Tg6799 mice treated with clusterin. Immunocytochemistry and quantitative analysis revealed that intraventricular (icv) administration of clusterin peptide in Tg6799 mouse reduced Aβ plaques as well the severity of cerebral amyloid angiopathy. Enzyme-linked immunosorbent assay demonstrated a decreased in the soluble levels of Aβ (Aβ40 and Aβ42) in the brain. Western-blot revealed an increased level of LRP-2 after clusterin peptide treatment.
These results suggest that icv infusion of clusterin peptide D-[113-122] offers a promising therapeutic approach to reduce Aβ deposition as well as CAA. The LRP2-mediated clearance system might be involved in the mechanism of these effects.
阿尔茨海默病（AD）的特征是淀粉样蛋白-β（Aβ）在脑实质和脑血管中沉积，形成脑淀粉样血管病（CAA）。载脂蛋白 E（clusterin）是一种与 Aβ聚集、毒性和通过血脑屏障运输相关的伴侣蛋白，可能在 AD 的发展中起关键作用。最近，clusterin 肽 D-[113-122]被证明可以模拟 clusterin 的功能，并在动脉粥样硬化中发挥治疗作用。在这项研究中，我们研究了这种 clusterin 肽是否也会影响 AD 转基因小鼠中的（Aβ）沉积。
使用微泵，将 clusterin 蛋白的合成肽 113-122（20μg/200μl）输注到 8 月龄 5×FAD 转基因小鼠模型（Tg6799）的侧脑室中，持续 2 周。水迷宫测试显示，接受 clusterin 治疗的 Tg6799 小鼠的认知功能得到改善。免疫细胞化学和定量分析显示，侧脑室给予 clusterin 肽可减少 Tg6799 小鼠的 Aβ斑块和脑淀粉样血管病的严重程度。酶联免疫吸附试验显示，脑内可溶性 Aβ（Aβ40 和 Aβ42）水平降低。Western blot 显示，clusterin 肽处理后 LRP-2 水平升高。
这些结果表明，侧脑室输注 clusterin 肽 D-[113-122]为减少 Aβ沉积和 CAA 提供了一种有前途的治疗方法。LRP2 介导的清除系统可能参与了这些作用的机制。
