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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
- Source :
- Experimental neurology 317 (2019): 51–65. doi:10.1016/j.expneurol.2019.02.014, info:cnr-pdr/source/autori: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./titolo: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/doi:10.1016%2Fj.expneurol.2019.02.014/rivista:Experimental neurology/anno:2019/pagina_da:51/pagina_a:65/intervallo_pagine:51–65/volume:317, Experimental neurology 317 (2019): 51–65. doi:10.1016/j.expneurol.2019.02.014., info:cnr-pdr/source/autori: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./titolo: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/doi:10.1016%2Fj.expneurol.2019.02.014./rivista:Experimental neurology/anno:2019/pagina_da:51/pagina_a:65/intervallo_pagine:51–65/volume:317
- Publication Year :
- 2018
-
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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 10902430
- Volume :
- 317
- Database :
- OpenAIRE
- Journal :
- Experimental neurology
- Accession number :
- edsair.doi.dedup.....80465e25febfc915c89fb1554b9bdaad