Isoform-specific effects of apolipoproteins E2, E3, and E4 on cerebral capillary sequestration and blood-brain barrier transport of circulating Alzheimer's amyloid beta.
Cerebral capillary sequestration and blood-brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sA beta(1-40), a peptide homologous to the major form of soluble Alzheimer's amyloid beta, were studied in perfused guinea pig brain. Cerebrovascular uptake of three apoE isoforms was low, their blood-to-brain transport undetectable, but uptake by the choroid plexus significant. Binding of all three isoforms to sA beta(1-40) in vitro was similar with a K(D) between 11.8 and 12.9 nM. Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sA beta(1-40)-apoE2 and sA beta(1-40)-apoE3, but significant for sA beta(1-40)-apoE4. After 10 min, 85% of sA beta(1-40)-apoE4 taken up at the BBB remained as intact complex, whereas free sA beta(1-40) was 51% degraded. Circulating apoE isoforms have contrasting effects on cerebral capillary uptake of and BBB permeability of sA beta. ApoE2 and apoE3 completely prevent cerebral capillary sequestration and blood-to-brain transport of sA beta(1-40). Conversely, apoE4, by entering brain microvessels and parenchyma as a stable complex with sA beta, reduces peptide degradation and may predispose to cerebrovascular and possibly enhance parenchymal amyloid formation under pathological conditions.
Martel
C L
CL
Department of Neurological Surgery, Childrens Hospital Los Angeles, USC School of Medicine, California, U.S.A.
Mackic
J B
JB
Matsubara
E
E
Governale
S
S
Miguel
C
C
Miao
W
W
McComb
J G
JG
Frangione
B
B
Ghiso
J
J
Zlokovic
B V
BV
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000097:blood / Q000493:pharmacokinetics*; D016564:Amyloid beta-Protein Precursor / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D002199:Capillary Permeability; D002560:Cerebrovascular Circulation; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000097:blood / Q000493:pharmacokinetics*; D010477:Perfusion; D011994:Recombinant Proteins / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D010446:Peptide Fragments; D011994:Recombinant Proteins