title: Aβ Induces Excitotoxicity Mediated by APC/C-Cdh1 Depletion That Can Be Prevented by Glutaminase Inhibition Promoting Neuronal Survival.
abstract: 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 (Aβ), 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 Ca(2+) dysregulation, resulting in neuronal apoptosis. Glutaminase inhibition prevents glutamate excitotoxicity and apoptosis in Aβ 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 Aβ or glutamate in the CA1 region of the rat hippocampus. We show here for the first time in vivo that both Aβ 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.
authors: Department of Physiology, Faculty of Medicine, University of Valencia, INCLIVA Avda. Blasco Ibañez 15, 46010 Valencia, Spain.
authors: T
authors: T
authors: Fuchsberger
authors: Department of Anatomy and Human Embriology, Faculty of Medicine, University of Valencia, Avda. Blasco Ibañez 15, 46010 Valencia, Spain.|Department of Cellular Biology and Parasitology, Faculty of Biology, University of Valencia, Avda. Doctor Moliner 50, 46100 Valencia, Spain.
authors: S
authors: S
authors: Martínez-Bellver
authors: Department of Physiology, Faculty of Medicine, University of Valencia, INCLIVA Avda. Blasco Ibañez 15, 46010 Valencia, Spain.
authors: E
authors: E
authors: Giraldo
authors: Department of Anatomy and Human Embriology, Faculty of Medicine, University of Valencia, Avda. Blasco Ibañez 15, 46010 Valencia, Spain.
authors: V
authors: V
authors: Teruel-Martí
authors: Department of Physiology, Faculty of Medicine, University of Valencia, INCLIVA Avda. Blasco Ibañez 15, 46010 Valencia, Spain.
authors: A
authors: A
authors: Lloret
authors: Department of Physiology, Faculty of Medicine, University of Valencia, INCLIVA Avda. Blasco Ibañez 15, 46010 Valencia, Spain.
authors: J
authors: J
authors: Viña
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D064200:Cdh1 Proteins / Q000378:metabolism*; D002470:Cell Survival; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D005972:Glutaminase / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016229:Amyloid beta-Peptides; D064200:Cdh1 Proteins; D064173:Anaphase-Promoting Complex-Cyclosome; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D046988:Proteasome Endopeptidase Complex; D005972:Glutaminase