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

Abstract

BackgroundAge 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.MethodsThis 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.ResultsThere 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.ConclusionsAge-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.

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans

“…At the ependyma and pia, molecules such as HVA and 5-HIAA diffuse out of ECSB into CSF for removal by carriermediated transport and bulk flow.In Alzheimer"s disease, the concentration of A 42 in CSF is on average lower than in normal age-matched controls. Active carrier-mediated transport processes that remove A from CSF (Pascale et al, 2011) do not resemble the passive lymph circulation.…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…Similarly, the bidirectional transporter LRP-2 and influx transporter RAGE were decreased and unchanged with age, respectively. 139 These changes were associated with decreased concentrations of Ab42 in the CP, suggesting that the BCSFB compensates for agedependent transporter dysfunctions in the BBB. 139 In humans with AD, increased Ab deposition in the CP is observed.…”

“…139 These changes were associated with decreased concentrations of Ab42 in the CP, suggesting that the BCSFB compensates for agedependent transporter dysfunctions in the BBB. 139 In humans with AD, increased Ab deposition in the CP is observed. 140 Furthermore, Ab deposition in CP epithelial cells causes oxidative damage, disruption of the BCSFB, and cell death.…”

P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer's disease: preliminary observations

“…Recent research into sporadic Alzheimer's disease (AD) has confirmed that aging is the single most important risk factor for AD genesis, and that the accumulation of amyloid-beta (Ab) peptides as insoluble plaques and soluble oligomeric and intermediate forms are responsible for oxidative damage to neurons, eventually leading to neuronal death (Querfurth and LaFerla, 2010). More importantly, it has been shown that the accumulation of amyloid is not due to increased production, but rather to decreased clearance of Ab from the brain (Mawuenyega et al, 2010).…”