Reduction of histone cytotoxicity by the Alzheimer beta-amyloid peptide precursor.
In a search for Alzheimer beta-amyloid peptide precursor ligands, Potempska et al. (Arch. Biochem. Biophys. (1993) 304, 448) found that histones 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-amyloid peptide precursor (U-937) to those on cells that produce twenty times as much precursor (COS-7). Addition of purified histones caused necrosis of U-937 cells (histone H4, LD50 = 1.5 microM). Extracellular A beta precursor in the submicromolar range prevented histone-induced U-937 cell necrosis. Cell-surface precursor also reduced histone toxicity: COS-7 cells were less sensitive to the toxic effects of histone H4 (LD50 = 5.4 microM). COS-7 cells in which the expression of an APP mRNA-directed ribozyme reduced the synthesis of the protein by up to 80% were more sensitive to histone H4 (LD50 = 3.2 microM) than cells that expressed the vector alone. Histone H4 binds to cell-associated A beta precursor. Cells expressing the A beta precursor-directed ribozyme bound less 125I-labeled histone H4 than those expressing the vector alone. In the limited extracellular space of tissues in vivo, both secreted and cell-surface A beta precursor protein may play significant roles in trapping chromatin or histones and removing them from the extracellular milieu.
Currie
J R
JR
Laboratory of Developmental Neuromorphology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, USA. curriejr@interport.net
Chen-Hwang
M C
MC
Denman
R
R
Smedman
M
M
Potempska
A
A
Ramakrishna
N
N
Rubenstein
R
R
Wisniewski
H M
HM
Miller
D L
DL
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004396:Coloring Agents / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006657:Histones / Q000378:metabolism / Q000494:pharmacology*; D010078:Oxazines; D016337:RNA, Catalytic / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection / Q000235:genetics; D014966:Xanthenes
D016564:Amyloid beta-Protein Precursor; D004396:Coloring Agents; D006657:Histones; D010078:Oxazines; D016337:RNA, Catalytic; D012333:RNA, Messenger; D014966:Xanthenes; C005843:resazurin