BACKGROUND The role of environmental factors in Alzheimer's disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain β-amyloid (Aβ) deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. OBJECTIVES This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. METHODS Female APP/PS1 mice at 8 wk of age were administered either 50mg/kg Pb-acetate (PbAc) (i.e., 27mg Pb/kg) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immunostaining. In addition, Aβ perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed in vivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. RESULTS APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to Aβ40, higher Aβ40/Aβ42 ratios, strikingly lower Aβ40 levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. DISCUSSION Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders. https://doi.org/10.1289/EHP14384.

中文翻译：

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醋酸铅暴露和脑淀粉样蛋白积累：APP/PS1 小鼠的机制评估。


背景 环境因素在阿尔茨海默病 （AD） 发病机制中的作用仍然难以捉摸。越来越多的证据表明，急性和既往暴露于环境有毒物质铅 （Pb） 与认知功能的纵向下降、脑萎缩和脑 β-淀粉样蛋白 （Aβ） 沉积增加有关。然而，Pb 诱导的淀粉样蛋白沉积的性质及其如何促进 AD 的发展仍不清楚。目的 本研究探讨 Pb 在脑淀粉样血管病 （CAA） 发病机制中的作用，以及纤溶酶原激活物抑制剂 1 （PAI-1） 是否有助于 APP/PS1 小鼠模型中的这一过程。方法 通过口服强饲法给予 8 周龄的雌性 APP/PS1 小鼠 50 mg/kg 乙酸铅 （PbAc） （即 27 mg Pb/kg） 或同等摩尔浓度的乙酸钠 （NaAc），每天一次，持续 8 周。通过免疫染色测定淀粉样蛋白沉积和血管淀粉样蛋白。此外，检查 Aβ 血管周围引流、血管结合测定和小胶质细胞内吞作用以确定潜在机制。此外，进行磁共振成像脱髓鞘成像 体内测量脱髓鞘水平。最后，评估 Y 迷宫和 Morris 水迷宫测试以评估小鼠的认知功能。结果 暴露于 PbAc 的 APP/PS1 小鼠 （AD 小鼠模型） 表现出更多的血管淀粉样蛋白沉积、更少的新皮质髓鞘形成和较低的认知功能，以及更强的血管与 Aβ40 的结合、较高的 Aβ40/Aβ42 比率、血管周围引流中 Aβ40 水平显着降低和小胶质细胞内吞作用。 重要的是，暴露于特异性 PAI-1 抑制剂 tiplaxtinin，以前报道可降低小鼠的 CAA 病理学，导致 PbAc 暴露后 CAA 相关结果减少。讨论我们的研究结果表明，PbAc 在 APP/PS1 小鼠模型中通过 PAI-1 信号传导诱导 CAA/AD 发病机制，抑制 PAI-1 可能是 PbAc 介导的 CAA/AD 疾病的潜在治疗靶点。https://doi.org/10.1289/EHP14384。