Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer's amyloid beta.
Amyloid beta (A beta) is a fibrillar component in Alzheimers' disease amyloid deposits and a soluble peptide (sA beta) normally present in body fluids. We have recently reported that the blood-brain barrier (BBB) has a capability to control cerebrovascular sequestration and transport of circulating sA beta. In this study, we examined whether two circulating amyloid-associated proteins shown to bind sA beta, apolipoproteins J (apo J) and E (apo E), can cross the BBB alone and/or complexed to a synthetic peptide homologous to a major form of sA beta, sA beta 1-40. Brain perfusion experiments in guinea pigs showed significant uptake of both apo J and sA beta 1-40-apo J complexes. In contrast, blood-brain transport of sA beta 1-40-apo E was negligible, while apo E had a limited access across the BBB, indicating that the apo E found within the brain is produced locally. It is concluded that sA beta 1-40 binding to apo J and apo E results in significant (> 100-fold) difference in brain uptake of their respective complexes. We hypothesize that in normal brain apo J facilitates sA beta transport.
Zlokovic
B V
BV
Department of Neurological Surgery, Childrens Hospital Los Angeles, USC School of Medicine 90033.
Martel
C L
CL
Mackic
J B
JB
Matsubara
E
E
Wisniewski
T
T
McComb
J G
JG
Frangione
B
B
Ghiso
J
J
D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000378:metabolism*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002196:Capillaries / Q000502:physiology; D002560:Cerebrovascular Circulation; D051152:Clusterin; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008833:Microcirculation / Q000502:physiology; D018832:Molecular Chaperones; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D010446:Peptide Fragments