REDUCTION OF HISTONE CYTOTOXICITY BY THE ALZHEIMER BETA-AMYLOID PEPTIDE PRECURSOR

In a search for Alzheimer beta-amyloid peptide precursor ligands, Pote mpska et al. (Arch. Biochem. Biophys. (1993) 303, 448) found that hist ones bind with high affinity and specificity to the secreted precursor . Because exogenous histones can be cytotoxic, we compared the effects of histones on the viability of cells which produce little beta-amylo id peptide precursor (U-937) to those on cells that produce twenty tim es as much precursor (COS-7). Addition of purified histones caused nec rosis of U-937 cells (histone H4, LD(50) = 1.5 mu M). Extracellular A beta precursor in the submicromolar range prevented histone-induced U- 937 cell necrosis. Cell-surface precursor also reduced histone toxicit y: COS-7 cells were less sensitive to the toxic effects of histone H4 (LD(50) = 5.4 mu M). COS-7 cells in which the expression of an APP mRN A-directed ribozyme reduced the synthesis of the protein by up to 80% were more sensitive to histone H4 (LD(50) = 3.2 mu M) than cells that expressed the vector alone. Histone H4 binds to cell-associated A beta precursor. Cells expressing the A beta precursor-directed ribozyme bo und less I-125-labeled histone H4 than those expressing the vector alo ne. In the limited extracellular space of tissues in vivo, both secret ed and cell-surface A beta precursor protein may play significant role s in trapping chromatin or histones and removing them from the extrace llular milieu.