V642I APP-inducible neuronal cells: a model system for investigating Alzheimer's disorders.
APP is a precursor of beta amyloid deposited in Alzheimer's disease (AD). Although genetic studies established that mutations in APP cause familial AD (FAD), the mechanism for neuronal death by FAD mutants has not been well understood. We established neuronal cells (F11/EcR/V642I cells) in which V642I APP was inducibly expressed by ecdysone. Treatment with ecdysone, but not vehicle, killed most cells within a few days, with rounding, shrinkage, and detachment as well as nuclear fragmentation. Death was suppressed by Ac-DEVD-CHO and pertussis toxin. Electron microscopic analysis revealed that apoptosis occurred in ecdysone-treated cells. V642I-APP-induced death was suppressed by the anti-AD factors estrogen and apoE2. These data demonstrate not only that expression of this FAD gene causes neuronal apoptosis, but that F11/EcR/V642I cells, the first neuronal cells with inducible FAD gene expression, provide a useful model system in investigating AD disorders.
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160, Japan.
T
T
Niikura
N
N
Murayama
Y
Y
Hashimoto
Y
Y
Ito
Y
Y
Yamagishi
M
M
Matsuoka
Y
Y
Takeuchi
S
S
Aiso
I
I
Nishimoto
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004440:Ecdysone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006822:Hybrid Cells; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009842:Oligopeptides / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D011987:Receptors, Steroid / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D016564:Amyloid beta-Protein Precursor; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C055469:ecdysone receptor; D004440:Ecdysone; D004958:Estradiol; D037342:Pertussis Toxin