期刊
BIOCHEMICAL JOURNAL
卷 355, 期 -, 页码 869-877出版社
PORTLAND PRESS LTD
DOI: 10.1042/bj3550869
关键词
fibrillogenesis; neurotoxicity
资金
- NIA NIH HHS [AG05134, AG14366] Funding Source: Medline
- NINDS NIH HHS [NS38328] Funding Source: Medline
In a Flemish kindred, an Ala(692) --> Gly amino acid substitution in the amyloid beta -protein precursor (A beta PP) causes a form of early-onset Alzheimer's disease (AD) which displays prominent amyloid angiopathy and unusually large senile plaque cores. The mechanistic basis of this Flemish form of AD is unknown. Previous in vitro studies of amyloid beta -protein (A beta) production in HEK-293 cells transfected with cDNA encoding Flemish A beta PP have shown that full-length [A beta (1-40)] and truncated [A beta (5-40) and A beta (11-40)] forms of A beta are produced. In an. effort to determine how these peptides might contribute to the pathogenesis of the Flemish disease, comparative biophysical and neurotoxicity studies were performed on wild-type and Flemish A beta (1-40), A beta (5-40) and A beta (11-40). The results revealed that the Flemish amino acid substitution increased the solubility of each form of peptide, decreased the rate of formation of thioflavin-T-positive assemblies, and increased the SDS-stability of peptide oligomers. Although the kinetics of peptide assembly were altered by the Ala(21) --> Gly substitution, all three Flemish variants formed fibrils, as did the wild-type peptides. Importantly, toxicity studies using cultured primary rat cortical cells showed that the Flemish assemblies were as potent a neurotoxin as were the wildtype assemblies. Our results are consistent with a pathogenetic process in which conformational changes in A beta induced by the Ala(21) --> Gly substitution would facilitate peptide adherence to the vascular endothelium, creating nidi for amyloid growth. Increased peptide solubility and assembly stability would favour formation of larger deposits and inhibit their elimination. In addition, increased concentrations of neurotoxic assemblies would accelerate neuronal injury and death.
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