RT Journal Article
SR Electronic
T1 Apolipoprotein E Genotype Regulates Amyloid-β Cytotoxicity
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3621
OP 3627
DO 10.1523/JNEUROSCI.4213-04.2005
VO 25
IS 14
A1 Micha M. M. Wilhelmus
A1 Irene Otte-Höller
A1 Judianne Davis
A1 William E. Van Nostrand
A1 Robert M. W. de Waal
A1 Marcel M. Verbeek
YR 2005
UL http://www.jneurosci.org/content/25/14/3621.abstract
AB The ϵ4 allele of apolipoprotein E (ApoE) is a risk factor for Alzheimer's disease (AD), whereas the ϵ2 allele may be relatively protective. Both alleles are risk factors for cerebral amyloid angiopathy (CAA)-related hemorrhages. CAA is associated with degeneration of smooth muscle cells and pericytes. Previously, we described that synthetic amyloid-β1-40 peptide (Aβ1-40) with the 22Glu→ Gln “Dutch” mutation caused pericyte death in vitro by a mechanism that involves Aβ fibril-like assembly at the cell surface. It is known that ApoE binds to Aβ and may modify its biological activities. In the present study, we evaluated the effect of ApoE on Aβ-mediated toxicity of cerebrovascular cells. We observed that cultured cells with an ϵ4/ϵ4 genotype were more vulnerable to Aβ than cultures with an ϵ3/ϵ3 or ϵ3/ϵ4 genotype. The one cell culture with the ϵ2/ϵ3 genotype was relatively resistant to Aβ compared with other cultures. Furthermore, we observed a dose-dependent protective effect of native ApoE against Aβ-mediated toxicity of cerebrovascular cells and, in addition, ApoE ϵ2/ϵ3 cells secreted more ApoE protein compared with cells with other ApoE genotypes, in particular, compared with ϵ4/ϵ4 cells. Thus, the disparity between ApoE genotype and Aβ-mediated toxicity might be related to differences in the cellular capacity to secrete ApoE. The present data suggest that one mechanism by which ApoE may alter the risk for AD is a genotype-dependent regulation of Aβ cytotoxicity, possibly via variations in its secretion levels, whereby extracellular ApoE may bind to Aβ and thereby modify Aβ-mediated cell death.