Amino- and carboxyl-terminal mutants of presenilin 1 cause neuronal cell death through distinct toxic mechanisms: Study of 27 different presenilin 1 mutants.
Presenilin (PS)1 and its mutants, which consist of the N-terminal and C-terminal fragments, cause certain familial forms of Alzheimer's disease (FAD). Our earlier studies found that FAD-linked M146L-PS1 causes neuronal cell death through nitrogen oxide synthase (NOS) and that FAD-linked N141I-PS2, another member of the PS family, causes neuronal cell death through NADPH oxidase. In this study, we examined 27 different FAD-linked mutants of PS1, and found that PS1 mutants with mutations in the N-terminal fragment caused NOS inhibitor (NOSI)-sensitive neuronal cell death; in contrast, the PS1 mutants with mutations in the C-terminal fragment caused NOSI-resistant neuronal cell death. The former toxicity was resistant to the specific NADPH oxidase inhibitor apocynin and was inhibited by Humanin (HN), a newly identified neuroprotective factor against Alzheimer's disease (AD)-relevant insults, but not by insulin-like growth factor-I (IGF-I). In contrast, the latter toxicity was sensitive to apocynin and inhibited by both IGF-I and HN. This study indicates for the first time that N- and C-terminal fragment PS1 mutants can generate distinct neurotoxic signals, which will provide an important clue to the understanding of the entire array of neurotoxic signals generated by FAD-causative mutations of PS1.
Hashimoto
Yuichi
Y
Department of Pharmacology, KEIO University School of Medicine, Tokyo, Japan.
Tsukamoto
Emi
E
Niikura
Takako
T
Yamagishi
Yohichi
Y
Ishizaka
Miho
M
Aiso
Sadakazu
S
Takashima
Akihiko
A
Nishimoto
Ikuo
I
D000098:Acetophenones / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000235:genetics / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D053764:Presenilin-1; D011506:Proteins / Q000494:pharmacology
D000098:Acetophenones; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D053764:Presenilin-1; D011506:Proteins; C427211:humanin; D007334:Insulin-Like Growth Factor I; C056165:acetovanillone; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases