Blood-brain barrier transport of circulating Alzheimer's amyloid beta.
The origin of amyloid beta (A beta) deposited in brain and cerebral blood vessels of patients with Alzheimer's Disease (AD) is not known. In this study, we tested whether soluble A beta (sA beta) can cross the blood-brain barrier (BBB). An in vivo vascular brain perfusion model and capillary depletion technique in guinea-pigs were used to determine cerebral capillary sequestration and blood-brain transport of a synthetic peptide identical with residues 1-40 (SP-40) of A beta. A saturable, specific binding of SP-40 has been demonstrated at the luminal side of the BBB, with the Kd of 25 +/- 2 nM, and Bmax of 188 +/- 11 fmol/min/g of isolated microvessels. A specific transcellular BBB transport of SP-40 into brain parenchyma exhibited the Km of 49 +/- 10 nM, and Vmax of 111 +/- 19 fmol/min/g of capillary depleted brain. We concluded that the BBB has the capability to control the cerebrovascular sequestration and blood-to-brain transport of circulating sA beta. Hence, sA beta can contribute to both cerebrovascular and parenchymal amyloid formation.
Zlokovic
B V
BV
Department of Neurological Surgery, Childrens Hospital, Los Angeles, USC School of Medicine 90033.
Ghiso
J
J
Mackic
J B
JB
McComb
J G
JG
Weiss
M H
MH
Frangione
B
B
D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002196:Capillaries / Q000502:physiology; D002250:Carbon Radioisotopes; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D008833:Microcirculation / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013395:Sucrose / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D002250:Carbon Radioisotopes; D007457:Iodine Radioisotopes; D010446:Peptide Fragments; D013395:Sucrose