School of Health Sciences, Purdue University, 550 Stadium Mall Drive, HAMP-1273, West Lafayette, IN, 47907, USA.
School of Public Health, Qingdao University, Qingdao, China.
Fluids Barriers CNS. 2023 May 1;20(1):32. doi: 10.1186/s12987-023-00432-5.
Lead (Pb) is a known environmental risk factor in the etiology of Alzheimer's disease (AD). The existing reports suggest that Pb exposure increases beta-amyloid (Aβ) levels in brain tissues and cerebrospinal fluid (CSF) and facilitates the formation of amyloid plaques, which is a pathological hallmark for AD. Pb exposure has long been associated with cerebral vasculature injury. Yet it remained unclear if Pb exposure caused excessive Ab buildup in cerebral vasculature, which may damage the blood-brain barrier and cause abnormal Ab accumulation. This study was designed to investigate the impact of chronic Pb exposure on Aβ accumulation in cerebral capillary and the expression of low-density lipoprotein receptor protein-1 (LRP1), a critical Aβ transporter, in brain capillary and parenchyma. Sprague-Dawley rats received daily oral gavage at doses of 0, 14 (low-dose), and 27 (high-dose) mg Pb/kg as Pb acetate, 5 d/wk, for 4 or 8 wks. At the end of Pb exposure, a solution containing Aβ was infused into the brain via the cannulated internal carotid artery. Data by ELISA showed a strikingly high affinity of Ab to cerebral vasculature, which was approximately 7-14 times higher than that to the parenchymal fractions collected from control brains. Pb exposure further aggravated the Aβ accumulation in cerebral vasculature in a dose-dependent manner. Western blot analyses revealed that Pb exposure decreased LRP1 expression in cortical capillaries and hippocampal parenchyma. Immunohistochemistry (IHC) studies further revealed a disrupted distribution of LRP1 alongside hippocampal vasculature accompanied with a decreased expression in hippocampal neurons by Pb exposure. Taken together, the current study demonstrated that the cerebral vasculature naturally possessed a high affinity to Aβ present in circulating blood. Pb exposure significantly increased Aβ accumulation in cerebral vasculature; such an increased Aβ accumulation was due partly to the diminished expression of LRP1 in response to Pb in tested brain regions. Perceivably, Pb-facilitated Ab aggravation in cerebral vasculature may contribute to Pb-associated amyloid alterations.
铅 (Pb) 是阿尔茨海默病 (AD) 病因学中的已知环境风险因素。现有报告表明，Pb 暴露会增加脑组织和脑脊液 (CSF) 中的β-淀粉样蛋白 (Aβ) 水平，并促进淀粉样斑块的形成，这是 AD 的病理标志。Pb 暴露长期以来与脑血管损伤有关。然而，目前尚不清楚 Pb 暴露是否导致脑血管中 Ab 过度积聚，从而可能破坏血脑屏障并导致异常 Ab 积聚。本研究旨在研究慢性 Pb 暴露对脑毛细血管中 Aβ 积累的影响，以及低密度脂蛋白受体蛋白-1（LRP1）在脑毛细血管和实质中的表达，LRP1 是一种关键的 Aβ 转运蛋白。Sprague-Dawley 大鼠每天接受 0、14（低剂量）和 27（高剂量）mg Pb/kg 作为 Pb 醋酸盐的口服灌胃，每周 5 天，持续 4 或 8 周。在 Pb 暴露结束时，通过套管内颈动脉将含有 Aβ 的溶液输注到大脑中。ELISA 数据显示 Ab 对脑血管具有极高的亲和力，大约是从对照大脑收集的实质部分的 7-14 倍。Pb 暴露以剂量依赖性方式进一步加重了脑毛细血管中的 Aβ 积累。Western blot 分析显示，Pb 暴露降低了皮质毛细血管和海马实质中的 LRP1 表达。免疫组织化学（IHC）研究进一步显示，Pb 暴露破坏了海马血管周围的 LRP1 分布，并降低了海马神经元中的表达。综上所述，本研究表明，脑血管对循环血液中存在的 Aβ 具有天然的高亲和力。Pb 暴露显著增加了脑毛细血管中的 Aβ 积累；这种 Aβ 积累的增加部分归因于受测脑区中 LRP1 对 Pb 反应的表达减少。可以预见，Pb 促进的 Ab 在脑血管中的加重可能导致与 Pb 相关的淀粉样改变。
