Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD).
The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer's disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3-18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup) of [3H]cholesterol and [3H]Aβ1 - 40 was then evaluated in these mice, using the in situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ.
Laboratoire de Pharmacie Clinique et pharmacocinétique, EA 4123, Université Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France.
Tuan Minh
TM
Do
Inserm UMR-S1144, Paris, F 75006, France.|Université Paris Descartes, Paris, France.|Université Paris Diderot, Paris, France.
Agnès
A
Dodacki
Faculty of Pharmacy, Laval University, Quebec (QC), Canada.
Wael
W
Alata
Faculty of Pharmacy, Laval University, Quebec (QC), Canada.
Frederic
F
Calon
Inserm UMR-S1144, Paris, F 75006, France.|Université Paris Descartes, Paris, France.|Université Paris Diderot, Paris, France.
Sophie
S
Nicolic
Inserm UMR-S1144, Paris, F 75006, France.|Université Paris Descartes, Paris, France.|Université Paris Diderot, Paris, France.
Jean-Michel
JM
Scherrmann
Laboratoire de Pharmacie Clinique et pharmacocinétique, EA 4123, Université Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France.
Robert
R
Farinotti
Inserm UMR-S1144, Paris, F 75006, France.|Université Paris Descartes, Paris, France.|Université Paris Diderot, Paris, France.
Fanchon
F
Bourasset
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism*; D002247:Carbon Isotopes / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D013395:Sucrose / Q000378:metabolism; D014316:Tritium / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C487540:ABCG1 protein, mouse; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D016229:Amyloid beta-Peptides; D002247:Carbon Isotopes; D008074:Lipoproteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D014316:Tritium; D013395:Sucrose; D002784:Cholesterol; C095122:multidrug resistance protein 3
3xTg-AD; ABCA1; ABCB1; ABCG2; ABCG4; Alzheimer’s disease; Oatp1a4; RAGE; amyloid-β; blood-brain barrier; cholesterol