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).

TitleAge-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer's Disease (3xTg-AD).
Publication TypeJournal Article
Year of Publication2016
AuteursDo, TMinh, Dodacki, A, Alata, W, Calon, F, Nicolic, S, Scherrmann, J-M, Farinotti, R, Bourasset, F
JournalJ Alzheimers Dis
Volume49
Issue2
Pagination287-300
Date Published2016
ISSN1875-8908
KeywordsAging, Alzheimer Disease, Amyloid beta-Peptides, Animals, ATP Binding Cassette Transporter, Sub-Family B, ATP Binding Cassette Transporter, Sub-Family G, Member 1, ATP Binding Cassette Transporter, Sub-Family G, Member 2, ATP-Binding Cassette Transporters, Biological Transport, Blood-Brain Barrier, Brain, Carbon Isotopes, Cholesterol, Disease Models, Animal, Humans, Lipoproteins, Mice, Mice, Transgenic, Peptide Fragments, Receptors, LDL, Sucrose, Tritium, Tumor Suppressor Proteins
Abstract

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.

DOI10.3233/JAD-150350
Alternate JournalJ. Alzheimers Dis.
PubMed ID26484906
Grant ListMOP 102532 / / Canadian Institutes of Health Research / Canada