Deficiency of presenilin-1 increases calcium-dependent vulnerability of neurons to oxidative stress in vitro.
We examined the function of presenilin-1 (PS1) on neuronal resistance to oxidative stress. CNS neurons cultured from PS1-deficient mice exhibited increased vulnerability to H2O2 treatment compared with those from wild-type mice. Antioxidants protected the cultured neurons against the oxidative stress. An intracellular calcium chelator, BAPTA AM, as well as an L-type voltage-dependent calcium channel blocker, nifedipine, rescued the neurons from H2O2-induced death, while an N-type voltage-dependent calcium channel blocker, omega-conotoxin, or calcium release blockers from ER stores, dantrolene and xestospongin C, failed to rescue them. Wild-type and PS1-deficient neurons showed comparable increases of cytoplasmic free calcium levels after exposure to H2O2. Taken together with the data that PS1-deficient neurons exhibited increased vulnerability to glutamate, these findings imply that PS1 confers resistance to oxidative stress on neurons in calcium-dependent manners.
Nakajima
M
M
Department of Molecular Genetics, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Miura
M
M
Aosaki
T
T
Shirasawa
T
T
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010545:Peroxides / Q000494:pharmacology; D053764:Presenilin-1
D002614:Chelating Agents; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010545:Peroxides; D053764:Presenilin-1; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D018698:Glutamic Acid; D004533:Egtazic Acid; D002118:Calcium