Amyloid-beta (A beta) deposition in cerebral vessels (
cerebral amyloid angiopathy, CAA) is accompanied by degeneration of vascular cells, including pericytes and smooth muscle cells. Previous studies indicated that specific A beta
protein isoforms are toxic for cultured human brain pericytes and smooth muscle cells. In particular,
A beta 1-40 carrying the E22Q mutation, as in
hereditary cerebral hemorrhage with amyloidosis of the Dutch type (
HCHWA-D), is toxic. We investigated the effects of the A beta-
binding protein apolipoprotein E (
ApoE) on the toxicity of A beta for cultured human brain pericytes. We compared the toxicity of
HCHWA-D
A beta 1-40 for pericyte cultures with different
ApoE genotypes, studied the accumulation of A beta and
ApoE in these different cell cultures, and investigated the effects of exogenous
ApoE. Pericyte cultures with an
ApoE epsilon 2/epsilon 3 genotype were more resistant to
HCHWA-D
A beta 1-40 treatment than cultures with a epsilon 3/epsilon 3 or epsilon 3/epsilon 4 genotype. Cell death was highest in cultures homozygous for
ApoE epsilon 4. The extent to which both A beta
ApoE accumulated at the cell surface was parallel to the degree of toxicity. The addition of purified
ApoE resulted in a decrease in cell death. These data suggest that
ApoE4 may direct A beta more efficiently than other
ApoE isoforms into a pathological interaction with the HBP cell surface. The results of this study are in line with the observations that inheritance of the
ApoE epsilon 4 allele increases the risk of developing
Alzheimer's disease, and that the
ApoE epsilon 2 allele has a relatively protective effect.