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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 [Exp Neurol] 2019 Jul; Vol. 317, pp. 51-65. Date of Electronic Publication: 2019 Feb 26. - Publication Year :
- 2019
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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 <superscript>-/-</superscript> ) 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 <superscript>-/-</superscript> 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 <superscript>-/-</superscript> 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.<br /> (Copyright © 2019. Published by Elsevier Inc.)
- Subjects :
- Aged
Aged, 80 and over
Alzheimer Disease metabolism
Animals
Cognition Disorders psychology
D-Aspartate Oxidase genetics
Female
Humans
Mice
Mice, Knockout
Middle Aged
Neuronal Plasticity drug effects
Neurons drug effects
Phosphorylation drug effects
Pregnancy
Primary Cell Culture
Alzheimer Disease pathology
Cell Death drug effects
Cerebral Cortex pathology
D-Aspartate Oxidase metabolism
D-Aspartic Acid pharmacology
MAP Kinase Kinase 4 metabolism
Neurons pathology
Receptors, N-Methyl-D-Aspartate drug effects
Sumoylation drug effects
tau Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2430
- Volume :
- 317
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 30822420
- Full Text :
- https://doi.org/10.1016/j.expneurol.2019.02.014