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Isoform‐Specific Effects of Apolipoproteins E2, E3, and E4 on Cerebral Capillary Sequestration and Blood‐Brain Barrier Transport of Circulating Alzheimer's Amyloid β
Author(s) -
Martel Cynthia L.,
Mackic Jasmina B.,
Matsubara Etsuro,
Governale Samuel,
Miguel Calero,
Miao Wesley,
McComb J. Gordon,
Frangione Blas,
Ghiso Jorge,
Zlokovic Berislav V.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69051995.x
Subject(s) - choroid plexus , blood–brain barrier , parenchyma , apolipoprotein e , amyloid beta , chemistry , amyloid (mycology) , vascular permeability , gene isoform , pathology , endocrinology , medicine , central nervous system , peptide , biochemistry , biology , disease , gene
Cerebral capillary sequestration and blood‐brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sAβ 1–40 , a peptide homologous to the major form of soluble Alzheimer's amyloid β, 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 sAβ 1–40 in vitro was similar with a K D between 11.8 and 12.9 n M . Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sAβ 1–40 ‐apoE2 and sAβ 1–40 ‐apoE3, but significant for sAβ 1–40 ‐apoE4. After 10 min, 85% of sAβ 1–40 ‐apoE4 taken up at the BBB remained as intact complex, whereas free sAβ 1–40 was 51% degraded. Circulating apoE isoforms have contrasting effects on cerebral capillary uptake of and BBB permeability of sAβ. ApoE2 and apoE3 completely prevent cerebral capillary sequestration and blood‐to‐brain transport of sAβ 1–40 . Conversely, apoE4, by entering brain microvessels and parenchyma as a stable complex with sAβ, reduces peptide degradation and may predispose to cerebrovascular and possibly enhance parenchymal amyloid formation under pathological conditions.