Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood–cerebrospinal fluid barrier in human brain

Abstract

A large number of previous reports have focused on the transport of amyloid-β peptides through cerebral endothelial cells via the blood-brain barrier, while fewer reports have mentioned the transport through the choroid plexus epithelium via the blood-cerebrospinal fluid barrier. Concrete roles of these two pathways remain to be clarified. In this study, we immunohistochemically examined the expression of transporters/receptors that are supposed to be related to the clearance of amyloid-β peptides in the choroid plexus epithelium, the ventricular ependymal cells and the brain microvessels, using seven autopsied human brains. In the choroid plexus epithelium, immunoreactivity for low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), LRP2, formylpeptide receptor-like 1 (FPRL1), ATP-binding cassette (ABC) transporter-A1 (ABCA1), ABCC1 and ABCG4 was seen in 7 of 7 brains, while that for ABCB1, ABCG2, RAGE and CD36 was seen in 0-2 brains. In the ventricular ependymal cells, immunoreactivity for CD36, LDLR, LRP1, LRP2, FPRL1, ABCA1, ABCC1 and ABCG4 was seen in 6-7 brains, while that for ABCB1, ABCG2 and RAGE was seen in 0-1 brain. Immunoreactivity for insulin-degrading enzyme (IDE) was seen in three and four brains in the choroid plexus epithelium and the ventricular ependymal cells, respectively. In addition, immunoreactivity for LDLR, ABCB1 and ABCG2 was seen in over 40 % of the microvessels (all seven brains), and that for FPRL1, ABCA1, ABCC1 and RAGE was seen in over 5 % of the microvessels (4-6 brains), while that for CD36, IDE, LRP1, LRP2 and ABCG4 was seen in less than 5 % of the microvessels (0-2 brains). These findings may suggest that these multiple transporters/receptors and IDE expressed on the choroid plexus epithelium, ventricular ependymal cells and brain microvessels complementarily or cooperatively contribute to the clearance of amyloid-β peptides from the brain.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…The transporter ABCC1 may also restrict the penetration of plasma unconjugated bilirubin into CSF [45], and thus contribute to protect the brain in case of moderate transient hyperbilirubinemia, such as occurring in neonatal jaundice. The expression in the choroidal epithelium of ABCB1 and ABCG2, two hallmark transporters of the BBB, is debated [44,91,119]. Given their supposedly apical/subapical localization, these proteins would …”

Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

“…Transcripts have been detected in mouse choroid plexus [100] . A recent immunohistochemical analysis of the receptor in human choroid plexus showed consistent positive signal in choroidal epithelial cells across the whole series of tissues collected from seven patients [101]. Future studies evaluating the potential of LDL receptor-mediated transcytosis in CNS drug penetration should investigate in parallel the BBB and the BSCFB.…”

“…The receptor was immunodetected in mouse brain microvessels [110]. Conversely, LRP1 could not be detected at the BBB in human brain tissues [111, 112], or was detected in only two brain samples out of seven in a recent study on human tissue [101]. In chicken, only brain penetrating large vessels were mentioned as positively stained [113].…”

“…LRP1 has been immunolocalized more consistently in rat, chicken, and human choroid plexus, in which the signal apparently distributes at both apical and basolateral membranes, and in the cytosol of epithelial cells (Fig. 1C , and [101, 113, 115]). LRP1 immunosignal in rat was described as very intense on the choroid plexus epithelium, compared to peripheral organs or other cerebral structures [115].…”

“…LRP2 immunoreactivity was observed at the apical membrane of choroid plexus epithelial cells in 3-day-old rats [119]. The receptor was also immunodetected in the adult mouse, rat, and human choroid plexus, where it stained the whole epithelial cell [101, 120]. Functional studies in adult rats presenting a partial and localized LRP2 deficiency at the BCSFB following intraventricular injection of a lentiviral silencing vector have indicated that several LRP2 ligands are transcytosed from blood to CSF across the BCSFB [1].…”