Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent - PubMed (original) (raw)

Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent

Crissey L Pascale et al. Fluids Barriers CNS. 2011.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Figures

Figure 1

Figure 1

LRP-1 expression at the CP epithelium with age. (A) Graph of the log-transformed normalized expression of LRP-1 with age, n = 8 for each age group tested (4 rats, 8 CPs pooled for each "n", 32 rats for an n = 8). One-way ANOVA revealed a significant increase in LRP-1 expression (p = 0.047). Significance was reached between 9 and 30 mo 95% confidence limits (0.0122, 1.1828). Error bars represent 95% confidence intervals for the means_. (_B) Semi-quantitative IHC for LRP-1 expression in grayscale units (GU). Mean staining intensity was significantly different (_p <_0.05) for the six age groups, n = 5 for each age group (5 rats, 2 CPs for each sample). (C) IHC of LRP-1 expression at 3 mo (top), 30 mo (center) and 36 mo (bottom) old rats. Staining is localized to the apical membrane (arrows).

Figure 2

Figure 2

Expression of LRP-2 at the CP with age. (A) Graph of the log-transformed normalized expression of LRP-2 with respect to age, n = 8 per age group. One-way ANOVA revealed a significant decrease (p = 0.0005) with age on LRP-2 expression. Significance was reached between 3 and 9, 12, 20, 30, and 36 mo. Error bars represent 95% confidence intervals for the means. (B) Semi-quantitative IHC for LRP-2 expression in grayscale units (GU). Mean staining intensity was significantly decreased (_p <_0.05) for the age groups, n = 5 per age group. (C) IHC of LRP-2 expression at 3 mo (top), 20 mo (center), and 36 mo (bottom) old rats. Staining is localized to the apical membrane (arrows), and is also seen subapically.

Figure 3

Figure 3

Age-related P-gp expression at the CP. (A) Graph of the log-transformed normalized expression of P-gp with respect to age, n = 8 for each age group. One-way ANOVA revealed a significant increase (p = 0.0005) with age on P-gp expression. Significance was reached between 30 mo and 3, 6, 9, and 12 mo, and between 36 mo and 6 mo. Error bars represent 95% confidence intervals for the means. (B) Semi-quantitative IHC for P-gp expression. Stain area to tissue area ratio was not significantly different (p > 0.05) for the six age groups, n = 5 per age group. (C) IHC of P-gp expression at 3 mo (top), 20 mo (center), and 36 mo (bottom) old rats. Majority of staining is localized to the basolateral membrane (arrows), though on occasion it is seen along the apical membrane (asterisk).

Figure 4

Figure 4

Aβ42 concentration in the CP epithelium with age. (A) Semi-quantitative IHC for Aβ42 deposition. Mean staining intensity in grayscale units (GU) was significantly decreased (p < 0.05) for the age groups, n = 5 per age group. (B) IHC of Aβ42 at 3 mo (left), 20 mo (center), and 36 mo (right) old rats. Staining is granular and primarily cytosolic (asterisks), though also found along the apical membrane (arrows).

Figure 5

Figure 5

Diagrams of the direction and expression of the Aβ transporters at the BCSFB. (A) Diagram to show the direction and relative expression of LRP-1, P-gp and LRP-2 at three months of age in the BN/F rat. (B) Diagram of the relative expression of the three transporters after 20 months. Note that LRP-1 and P-gp expression increase, whereas LRP-2 expression decreases with age.

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