1. Free d-aspartate triggers NMDA receptor-dependent cell death in primary cortical neurons and perturbs JNK activation, Tau phosphorylation, and protein SUMOylation in the cerebral cortex of mice lacking d-aspartate oxidase activity
- Author
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Ilaria Pagano, Daniela Punzo, Loredano Pollegioni, Marco Feligioni, Luigia Cristino, Massimo Carella, Paolo de Girolamo, Filomena Iannuzzi, Serena Marcelli, Carla Petrella, Francesco Errico, Nadia Canu, Livia D'Angelo, Roberta Imperatore, Alessandro Usiello, Silvia Sacchi, Tommaso Nuzzo, Nuzzo, T, Feligioni, M, Cristino, L, Pagano, I, Marcelli, S, Iannuzzi, F, Imperatore, R, D'Angelo, L, Petrella, C, Carella, M, Pollegioni, L, Sacchi, S, Punzo, D, De Girolamo, P, Errico, F, Canu, N, Usiello, A, Nuzzo, T., Feligioni, M., Cristino, L., Pagano, I., Marcelli, S., Iannuzzi, F., Imperatore, R., D'Angelo, L., Petrella, C., Carella, M., Pollegioni, L., Sacchi, S., Punzo, D., De Girolamo, P., Errico, F., Canu, N., Usiello, A., and Errico, Francesco
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0301 basic medicine ,Aging ,D-Aspartate Oxidase ,MAP Kinase Kinase 4 ,Hippocampus ,Mouse models ,Mice ,0302 clinical medicine ,Alzheimer's disease ,JNK ,NMDA receptor ,SUMOylation ,Tau ,d-aspartate ,d-aspartate oxidase ,?-Amiloyd ,Pregnancy ,Phosphorylation ,Aged, 80 and over ,Cerebral Cortex ,Mice, Knockout ,Neurons ,Neuronal Plasticity ,Cell Death ,Chemistry ,D-Aspartic Acid ,D-aspartate ,Middle Aged ,Cell biology ,medicine.anatomical_structure ,Neurology ,Cerebral cortex ,microscopy ,Female ,β-Amiloyd ,Protein sumoylation ,D-aspartate oxidase ,Developmental Neuroscience ,d-aspartato ,brain ,Primary Cell Culture ,Substantia nigra ,tau Proteins ,Settore BIO/09 ,Receptors, N-Methyl-D-Aspartate ,Mouse model ,03 medical and health sciences ,Alzheimer Disease ,medicine ,Animals ,Humans ,Aged ,Pars compacta ,Sumoylation ,istochemistry ,030104 developmental biology ,Synaptic plasticity ,d-aminoacidi ,Cognition Disorders ,030217 neurology & neurosurgery - Abstract
In mammals, free d-aspartate (D-Asp) is abundant in the embryonic brain, while levels remain very low during adulthood as a result of the postnatal expression and activity of the catabolizing enzyme d-aspartate oxidase (DDO). Previous studies have shown that long-lasting exposure to nonphysiological, higher D-Asp concentrations in Ddo knockout (Ddo-/-) mice elicits a precocious decay of synaptic plasticity and cognitive functions, along with a dramatic age-dependent expression of active caspase 3, associated with increased cell death in different brain regions, including hippocampus, prefrontal cortex, and substantia nigra pars compacta. Here, we investigate the yet unclear molecular and cellular events associated with the exposure of abnormally high D-Asp concentrations in cortical primary neurons and in the brain of Ddo-/- mice. For the first time, our in vitro findings document that D-Asp induces in a time-, dose-, and NMDA receptor-dependent manner alterations in JNK and Tau phosphorylation levels, associated with pronounced cell death in primary cortical neurons. Moreover, observations obtained in Ddo-/- animals confirmed that high in vivo levels of D-Asp altered cortical JNK signaling, Tau phosphorylation and enhanced protein SUMOylation, indicating a robust indirect role of DDO activity in regulating these biochemical NMDA receptor-related processes. Finally, no gross modifications in D-Asp concentrations and DDO mRNA expression were detected in the cortex of patients with Alzheimer's disease when compared to age-matched healthy controls. In mammals, free D-aspartate (D-Asp) is abundant in the embryonic brain, while levels remain very low during adulthood as a result of the postnatal expression and activity of the catabolizing enzyme D-aspartate oxidase (DDO). Previous studies have shown that long-lasting exposure to nonphysiological, higher D-Asp concentrations in Ddo knockout (Ddo(-/-)) mice elicits a precocious decay of synaptic plasticity and cognitive functions, along with a dramatic age-dependent expression of active caspase 3, associated with increased cell death in different brain regions, including hippocampus, prefrontal cortex, and substantia nigra pars compacta. Here, we investigate the yet unclear molecular and cellular events associated with the exposure of abnormally high D-Asp concentrations in cortical primary neurons and in the brain of Ddo(-/-) mice. For the first time, our in vitro findings document that D-Asp induces in a time-, dose-, and NMDA receptor-dependent manner alterations in JNK and Tau phosphorylation levels, associated with pronounced cell death in primary cortical neurons, Moreover, observations obtained in Ddo(-/-) animals confirmed that high in vivo levels of D-Asp altered cortical JNK signaling, Tau phosphorylation and enhanced protein SUMOylation, indicating a robust indirect role of DDO activity in regulating these biochemical NMDA receptor-related processes. Finally, no gross modifications in D-Asp concentrations and DDO mRNA expression were detected in the cortex of patients with Alzheimer's disease when compared to age-matched healthy controls.
- Published
- 2018
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