Oatp1a4 and an L-Thyroxine-Sensitive Transporter Mediate the Mouse Blood-Brain Barrier Transport of Amyloid-β Peptide

Abstract

The influx of amyloid-β peptide (Aβ) across the blood-brain barrier is partly mediated by the receptor for advanced glycation end products (RAGE). But other transporters, like Oatp (organic anion transporter polypeptide, SLC21) transporters, could also be involved. We used in situ brain perfusion to show that rosuvastatin and taurocholate, two established Oatp1a4 substrates, decreased (5-fold) the Clup of [3H]Aβ while L-thyroxine increased it (5.5-fold). We demonstrated an interaction between Aβ and Oatp1a4 by co-immunoprecipitation and western blotting experiments, supporting the hypothesis that the rosuvastatin- and taurocholate-sensitive transporter was Oatp1a4. In conclusion, our results suggest that, in mice, the brain uptake of Aβ is partly mediated by Oatp1a4 and that L-thyroxine may play a crucial role in the inhibition of brain Aβ clearance.

Peripheral complement interactions with amyloid β peptide: Erythrocyte clearance mechanisms

“…Multiple studies have made clear that amyloid β peptide (Aβ) can move from brain to the peripheral circulation [e.g., 1–3] and from the peripheral circulation to brain [e.g., 4,5]. As such, the disposition of circulating Aβ may be pathophysiologically important.…”

Synthesis and Evaluation of [18F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts

“…19 Although in mice it has been suggested that the organic anion transporter polypeptide (Oatp1a4) is responsible for importing Aβ into the CNS, no comparable transporter has been identified in humans. 20 Therefore this loss of BBB integrity may simply lead to an increase in the influx of Aβ into the brain. Moreover, RAGE-dependent signaling mediates downregulation of exporters of Aβ, 21 upregulation of β-secretase, 22 neuroinflammatory responses, 23 and stimulates tau phosphorylation.…”

Thyroxine transfer from cerebrospinal fluid into choroid plexus and brain is affected by brefeldin A, low sodium, BCH, and phloretin, in ventriculo-cisternal perfused rabbits

“…In the presence of TA, the uptake of 125 I-T 4 into some brain tissues, such as ER and CAP, was increased. This suggests an interaction between TA and OATP 1a4 since TA was proven to be an OATP 1a4 substrate and sensitive transporter (Do et al, 2013 ). This agrees with a previous study which demonstrated that OATP2 and OATP3 mediate TH transport when their mRNA is injected into xenopus oocytes (Abe et al, 2002 ).…”

“…Previous research has concentrated on studying the transport direction of T 4 from blood into the brain across the BBB suggesting a role for organic anion transporting polypeptides (OATP) such as OATP 1a4, 1c1, 2, 3, and 14, which are mainly localized at the blood side of the BBB (Abe et al, 1998 ; Gao and Meier, 2001 ; Mayerl et al, 2012 ; Do et al, 2013 ) and CP (Gao et al, 1999 ; Gao and Meier, 2001 ; Mayerl et al, 2012 ). On the other hand, others have demonstrated a role for OATP2 and multiple drug resistance 1 (MDR1) in the transport of 125 I-T 4 at the basolateral side of the isolated perfused sheep CPs (Preston and Segal, 1992 ).…”