Isoform-Specific Effects of Apolipoproteins E2, E3, and E4 on Cerebral Capillary Sequestration and Blood-Brain Barrier Transport of Circulating Alzheimer's Amyloid β
Article first published online: 18 NOV 2002
Journal of Neurochemistry
Volume 69, Issue 5, pages 1995–2004, November 1997
How to Cite
Martel, C. L., Mackic, J. B., Matsubara, E., Governale, S., Miguel, C., Miao, W., McComb, J. G., Frangione, B., Ghiso, J. and Zlokovic, B. V. (1997), Isoform-Specific Effects of Apolipoproteins E2, E3, and E4 on Cerebral Capillary Sequestration and Blood-Brain Barrier Transport of Circulating Alzheimer's Amyloid β. Journal of Neurochemistry, 69: 1995–2004. doi: 10.1046/j.1471-4159.1997.69051995.x
- Issue published online: 18 NOV 2002
- Article first published online: 18 NOV 2002
- Received May 26, 1997; revised manuscript received June 19, 1997; accepted June 20, 1997.
- Apolipoprotein E;
- Amyloid β;
- Alzheimer's disease;
- Cerebrovascular sequestration;
- Blood-brain barrier;
Abstract: Cerebral capillary sequestration and blood-brain barrier (BBB) permeability to apolipoproteins E2 (apoE2), E3 (apoE3), and E4 (apoE4) and to their complexes with sAβ1–40, 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 sAβ1–40 in vitro was similar with a KD between 11.8 and 12.9 nM. Transport into brain parenchyma and sequestration by BBB and choroid plexus were negligible for sAβ1–40-apoE2 and sAβ1–40-apoE3, but significant for sAβ1–40-apoE4. After 10 min, 85% of sAβ1–40-apoE4 taken up at the BBB remained as intact complex, whereas free sAβ1–40 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 sAβ1–40. 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.