Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep31158
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Funding
- Spanish Ministry of Education and Science (MEC) [SAF2010-19498, SAF2013-44663-R]
- Red Tematica de investigacion cooperativa en envejecimiento y fragilidad (RETICEF) [ISCIII2012-RED-43-029]
- Conselleria d'Educacio, Cultura i Esport de la Generalitat Valenciana [PROMETEO2014/056]
- INCLIVA
- EU [CM1001, FRAILOMIC-HEALTH.2012.2.1.1-2]
- FEDER funds from the European Union
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The E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is activated by the fizzy-related protein homolog/CDC20-like protein 1 (cdh1) in post-mitotic neurons. Growing evidence suggests that dysregulation of APC/C-Cdh1 is involved in neurodegenerative diseases. Here we show in neurons that oligomers of amyloid beta (A beta), a peptide related to Alzheimer's disease, cause proteasome-dependent degradation of cdh1. This leads to a subsequent increase in glutaminase (a degradation target of APC/C-Cdh1), which causes an elevation of glutamate levels and further intraneuronal Ca2+ dysregulation, resulting in neuronal apoptosis. Glutaminase inhibition prevents glutamate excitotoxicity and apoptosis in A beta treated neurons. Furthermore, glutamate also decreases cdh1 and leads to accumulation of glutaminase, suggesting that there may be a positive feedback loop of cdh1 inactivation. We confirmed the main findings in vivo using microinjection of either A beta or glutamate in the CA1 region of the rat hippocampus. We show here for the first time in vivo that both A beta and glutamate cause nuclear exclusion of cdh1 and an increase in glutaminase. These results show that maintaining normal APC/C-Cdh1 activity may be a useful target in Alzheimer's disease treatment.
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