Selective neurotoxicity of COOH-terminal fragments of the beta-amyloid precursor protein.
The primary component of amyloid deposits found in the brains of patients with Alzheimer's disease is the beta-amyloid protein, a derivative of a much larger precursor protein (beta PP). We have previously reported that overexpression of carboxyl (COOH)-terminal fragments of beta PP from an integrated DNA construct leads to degeneration of neuronally differentiating mouse embryonic stem cells and that the neuronal degeneration is related to approximately 14- and 15-kDa COOH-terminal fragments of the precursor protein. We here demonstrate that these putative cytotoxic fragments contain intact beta-amyloid protein. When such transformed cell lines are treated with dimethyl sulfoxide to induce differentiation into muscle cells, however, the resulting muscle cells remain viable (as do control non-transformed cells), despite the production of comparable amounts of the 14- and 15-kDa fragments. These results are consistent with the hypothesis that particular COOH-terminal fragments of beta PP are amyloidogenic and neurotoxic.
Fukuchi
K
K
Department of Pathology, University of Washington, Seattle 98195.
Sopher
B
B
Furlong
C E
CE
Smith
A C
AC
Dang
N
N
Martin
G M
GM
D016564:Amyloid beta-Protein Precursor / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D009218:Myosins / Q000096:biosynthesis; D009410:Nerve Degeneration / Q000502:physiology; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D009218:Myosins; D004121:Dimethyl Sulfoxide