Isoform‐Specific Effects of Apolipoproteins E2, E3, and E4 on Cerebral Capillary Sequestration and Blood‐Brain Barrier Transport of Circulating Alzheimer's Amyloid β

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.

IgG-Assisted Age-Dependent Clearance of Alzheimer's Amyloid β Peptide by the Blood–Brain Barrier Neonatal Fc Receptor

“…The mechanism of peripheral A␤ sequestration observed in the present study with 4G8 in APPsw ϩ/Ϫ mice may be similar to that of other A␤ binding agents, i.e., apolipoproteins E2 and 3 (Martel et al, 1997), ganglioside M and gelsolin , the soluble forms of RAGE (Deane et al, 2003) or LRP , and/or other antibodies to A␤ that reduce its influx across the BBB (Pan et al, 2002;Banks et al, 2005). This peripheral binding of A␤ may create a sink effect, providing that the activity of the LRP efflux pathway is not lost or is sufficient to maintain elimination of brain A␤ and A␤-IgG complexes.…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…The ApoE production occurs in both the CNS and peripheral compartments, where it is made primarily by astrocytes and the liver, respectively. 201 An early pharmacokinetic study in guinea pigs showed that circulating ApoE does not cross the BBB, 202 and all three ApoE isoforms limit the influx of circulating Ab. 202,203 Unlike Ab in complex with ApoE2 and 3, circulating ApoE4-Ab complexes can cross the BBB.…”

“…201 An early pharmacokinetic study in guinea pigs showed that circulating ApoE does not cross the BBB, 202 and all three ApoE isoforms limit the influx of circulating Ab. 202,203 Unlike Ab in complex with ApoE2 and 3, circulating ApoE4-Ab complexes can cross the BBB. 202 All isoforms of ApoE show significant efflux across the BBB, although at slower rates than both Ab 40 and Ab 42 .…”

“…202,203 Unlike Ab in complex with ApoE2 and 3, circulating ApoE4-Ab complexes can cross the BBB. 202 All isoforms of ApoE show significant efflux across the BBB, although at slower rates than both Ab 40 and Ab 42 . 204 Furthermore, the efflux rate of ApoE4 across the BBB is slower than that for ApoE2 and 3.…”

Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy

“…The longer 42-residue form, A~i31~2, is the major constituent of insoluble /3-amyloid fibrils of senile plaques (Masters et al, 1985). It has been hypothesized that tide (sA/3 1_40) (Zlokovic et a!., 1993) and its complexes with apolipoprotein J (apoJ) and apoE4 (Martel et a!., 1997). Blood-to-brain uptake of sA/31_40 and clearance from the CSF have been reported in rodents (Maness et al, 1994;GhersiEgea et a!., 1996;Poduslo et al, 1997).…”