Autoregulated paracellular clearance of amyloid-β across the blood-brain barrier.
The blood-brain barrier (BBB) is essential for maintaining brain homeostasis and protecting neural tissue from damaging blood-borne agents. The barrier is characterized by endothelial tight junctions that limit passive paracellular diffusion of polar solutes and macromolecules from blood to brain. Decreased brain clearance of the neurotoxic amyloid-β (Aβ) peptide is a central event in the pathogenesis of Alzheimer's disease (AD). Whereas transport of Aβ across the BBB can occur via transcellular endothelial receptors, the paracellular movement of Aβ has not been described. We show that soluble human Aβ(1-40) monomers can diffuse across the paracellular pathway of the BBB in tandem with a decrease in the tight junction proteins claudin-5 and occludin in the cerebral vascular endothelium. In a murine model of AD (Tg2576), plasma Aβ(1-40) levels were significantly increased, brain Aβ(1-40) levels were decreased, and cognitive function was enhanced when both claudin-5 and occludin were suppressed. Furthermore, Aβ can cause a transient down-regulation of claudin-5 and occludin, allowing for its own paracellular clearance across the BBB. Our results show, for the first time, the involvement of the paracellular pathway in autoregulated Aβ movement across the BBB and identify both claudin-5 and occludin as potential therapeutic targets for AD. These findings also indicate that controlled modulation of tight junction components at the BBB can enhance the clearance of Aβ from the brain.
Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland.
James
J
Keaney
Laboratory for Neurodegenerative Research, Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Dominic M
DM
Walsh
Laboratory for Neurodegenerative Research, Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Tiernan
T
O'Malley
Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland.
Natalie
N
Hudson
Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland.
Darragh E
DE
Crosbie
Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland.
Teresa
T
Loftus
Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland.
Florike
F
Sheehan
Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland.
Jacqueline
J
McDaid
Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland.
Marian M
MM
Humphries
UCD School of Veterinary Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. ; Ross University School of Veterinary Medicine, P. O. Box 334, Basseterre, St. Kitts, West Indies.
John J
JJ
Callanan
Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland.
Francesca M
FM
Brett
Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland.
Michael A
MA
Farrell
Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland.
Peter
P
Humphries
Smurfit Institute of Genetics, Lincoln Place Gate, Trinity College Dublin, Dublin 2, Ireland.
Matthew
M
Campbell