Toxicity of various amyloid beta peptide species in cultured human blood-brain barrier endothelial cells: Increased toxicity of Dutch-type mutant

The amyloid beta peptide (A beta) is the major component of the neuritic an d cerebrovascular amyloid plaques that are one of the characteristic featur es of Alzheimer's disease (AD). This peptide has been shown to be toxic to several relevant cell types, including neurons, cerebrovascular smooth musc le cells, and endothelial cells. We have studied the toxic effects of both soluble and aggregated species of A beta(1-40) and the mutation A beta(1-40 )Glu-->Gln(22), which is the major species deposited in the cerebrovascular blood vessels of victims of hereditary cerebral hemorrhage with amyloidosi s, Dutch type. We find that aggregates of both peptides, as well as of A be ta(1-42) and A beta(25-35), are toxic to cultured human cerebrovascular end othelial cells (hBEC) obtained from the brain of a victim of AD (at doses l ower than those that are toxic to CNS neurons or leptomeningeal smooth musc le cells). Soluble A beta(1-40) Gln(22) is equally toxic to hBEC, whereas w ild-type A beta(1-40) is toxic only at higher doses. This toxicity is seen at the lowest dose of A beta(1-40) Gln(22) used, 20 nM. The soluble A beta( 1-40)Gln(22) aggregates on the surface of the cells, in contrast to A beta( 1-40), and its toxicity can be blocked both by an inhibitor of free radical formation and by Congo red, which inhibits amyloid fibril formation. We di scuss the possibility that the enhanced toxicity of A beta(1-40)Gln(22) is mediated by a A beta receptor on the endothelial cells. J. Neurosci. Res. 6 0:804-810, 2000. (C) 2000 Wiley-Liss, Inc.