Warren Alpert Medical School Brown University, RI Hospital Department of Neurosurgery 593 Eddy St, Providence, RI 02903 USA.
Fluids Barriers CNS. 2011 Jul 8;8:21. doi: 10.1186/2045-8118-8-21.
Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is an accumulation of amyloid-beta peptides (Aβ) in both the AD brain and the normal aging brain. Clearance of Aβ from the brain occurs via active transport at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). With increasing age, the expression of the Aβ efflux transporters is decreased and the Aβ influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aβ transporters at the choroid plexus (CP) epithelium as a function of aging was the subject of this study.
This project investigated the changes in expression of the Aβ transporters, the low density lipoprotein receptor-related protein-1 (LRP-1), P-glycoprotein (P-gp), LRP-2 (megalin) and the receptor for advanced glycation end-products (RAGE) at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC) to measure transporter protein in isolated rat CP.
There was an increase in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aβ42 concentration in the CP, as measured by quantitative IHC, was associated with these Aβ transporter alterations.
Age-dependent alterations in the CP Aβ transporters are associated with a decrease in Aβ42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aβ clearance in aging.
年龄是包括阿尔茨海默病（AD）在内的许多神经退行性疾病的主要危险因素。在 AD 大脑和正常衰老大脑中都有淀粉样β肽（Aβ）的积累。Aβ 从大脑中的清除是通过血脑屏障（BBB）和血脑脊液屏障（BCSFB）的主动转运来实现的。随着年龄的增长，Aβ 外排转运体的表达减少，而 BBB 上 Aβ 内流转运体的表达增加，导致大脑中的淀粉样负担增加。脉络丛（CP）上皮细胞中 Aβ 转运体随年龄的变化是本研究的主题。
本项目使用实时 RT-PCR 测量转运体 mRNA 表达，用免疫组化（IHC）测量分离大鼠 CP 中的转运体蛋白，研究了年龄在 3、6、9、12、20、30 和 36 个月的 Brown-Norway/Fischer 大鼠 BCSFB 中 Aβ 转运体、低密度脂蛋白受体相关蛋白-1（LRP-1）、P-糖蛋白（P-gp）、LRP-2（巨球蛋白）和晚期糖基化终产物受体（RAGE）的表达变化。
随着年龄的增长，Aβ 外排转运体 LRP-1 和 P-gp 的转录增加，RAGE 表达无变化，CP 上皮内流转运体 LRP-2 减少。通过定量 IHC 测量 CP 中的 Aβ42 浓度降低，与这些 Aβ 转运体改变有关。
CP Aβ 转运体的年龄依赖性改变与 CP 中 Aβ42 积累的减少有关，与 BBB 上这些转运体的变化相反，这表明 BCSFB 在衰老时可能对 Aβ 清除具有代偿作用。
