Beta-amyloid causes downregulation of calcineurin in neurons through induction of oxidative stress.
Calcineurin is an abundant cytosolic protein that is implicated in the modulation of glutamate release. Here we show that the expression level of this enzyme is reduced in primary neuronal cultures treated with beta-amyloid. Parallel experiments in ETNA cell lines expressing SOD1 suggested that the effect of beta-amyloid on calcineurin expression is mediated by oxidative stress. The relevance of the in vitro experiments was assessed by analysis of tissue from patients with Alzheimer's disease (AD) and tissue from two strains of transgenic mice that mimic aspects of AD. The tissue from the AD brains displayed a pronounced downregulation of calcineurin immunoreactivity in profiles that were negative for glial fibrillary acidic protein (GFAP). In the hippocampus of the transgenic animals (which were analyzed in an early stage of the disease) the downregulation of calcineurin was restricted to mossy fiber terminals. A downregulation of the presynaptic pool of calcineurin may contribute to the dysregulation of glutamate release that is considered a hallmark of AD.
Celsi
F
F
Laboratory of Molecular Neuroscience, Centre for Molecular Biology and Neuroscience, University of Oslo, Oslo, Norway. fulvio.celsi@gmail.com
Svedberg
M
M
Unger
C
C
Cotman
C W
CW
Carrì
M T
MT
Ottersen
O P
OP
Nordberg
A
A
Torp
R
R
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019703:Calcineurin / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
D016229:Amyloid beta-Peptides; C000606290:SOD1 protein, human; D018698:Glutamic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019703:Calcineurin