Evidence for a Strong Relationship between the Cytotoxicity and Intracellular Location of ß-Amyloid.

ß-Amyloid (Aß) is a hallmark peptide of Alzheimer's disease (AD). Herein, we explored the mechanism underlying the cytotoxicity of this peptide. Double treatment with oligomeric 42-amino-acid Aß (Aß42) species, which are more cytotoxic than other conformers such as monomers and fibrils, resulted in increased cytotoxicity. Under this treatment condition, an increase in intracellular localization of the peptide was observed, which indicated that the peptide administered extracellularly entered the cells. The cell-permeable peptide TAT-tagged Aß42 (tAß42), which was newly prepared for the study and found to be highly cell-permeable and soluble, induced Aß-specific lamin protein cleavage, caspase-3/7-like DEVDase activation, and high cytotoxicity (5-10-fold higher than that induced by the wild-type oligomeric preparations). Oligomeric species enrichment and double treatment were not necessary for enhancing the cytotoxicity and intracellular location of the fusion peptide. Taiwaniaflavone, an inhibitor of the cytotoxicity of wild-type Aß42 and tAß42, strongly blocked the internalization of the peptides into the cells. These data imply a strong relationship between the cytotoxicity and intracellular location of the Aß peptide. Based on these results, we suggest that agents that can reduce the cell permeability of Aß42 are potential AD therapeutics.