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

Abstract

The amyloid β peptide (Aβ) is the major component of the neuritic and cerebrovascular amyloid plaques that are one of the characteristic features of Alzheimer's disease (AD). This peptide has been shown to be toxic to several relevant cell types, including neurons, cerebrovascular smooth muscle cells, and endothelial cells. We have studied the toxic effects of both soluble and aggregated species of Aβ1–40 and the mutation Aβ1–40Glu→Gln22, which is the major species deposited in the cerebrovascular blood vessels of victims of hereditary cerebral hemorrhage with amyloidosis, Dutch type. We find that aggregates of both peptides, as well as of Aβ1–42 and Aβ25–35, are toxic to cultured human cerebrovascular endothelial cells (hBEC) obtained from the brain of a victim of AD (at doses lower than those that are toxic to CNS neurons or leptomeningeal smooth muscle cells). Soluble Aβ1–40 Gln22 is equally toxic to hBEC, whereas wild-type Aβ1–40 is toxic only at higher doses. This toxicity is seen at the lowest dose of Aβ1–40 Gln 22 used, 20 nM. The soluble Aβ1–40Gln22 aggregates on the surface of the cells, in contrast to Aβ1–40, and its toxicity can be blocked both by an inhibitor of free radical formation and by Congo red, which inhibits amyloid fibril formation. We discuss the possibility that the enhanced toxicity of Aβ1–40Gln22 is mediated by a Aβ receptor on the endothelial cells. J. Neurosci. Res. 60:804–810, 2000. © 2000 Wiley-Liss, Inc.