Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype.

[hereditary cerebral hemorrhage with amyloidosis]

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 E 22 Q 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 ApoE 4 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 .