N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Abstract

The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

Late stimulation of the sphenopalatine‐ganglion in ischemic rats: Improvement in N‐acetyl‐aspartate levels and diffusion weighted imaging characteristics as seen by MR

“…As shown previously, electrical stimulation of the SPG increases CBF in the infarct region (16). Because of the dependence of NAA synthesis on the energy levels in the cells (38,39), such a synthesis is reduced immediately after the ischemic event and the depletion of energy storage. Therefore, one can assume that the increase in NAA levels in the affected area may originate from the slow increase in the energy storage in these affected areas, which accumulated slowly as a result of the increase in the CBF occurring by the electrical stimulation of the SPG.…”

Diagnostic methods for extra-temporal neocortical focal epilepsies: present and future

“…The major energetic consumption occurs in an intermittent way, depending on physiologic needs, and so GABA also suffers variations along the day. Differently, in epileptic patients, it seems happen a disequilibrium of glutamine, glutamate (excitatory neurotransmitters) and GABA 49 , due to scarcity of glutamate transferase, and not to lack of substrate 56 .…”

“…To explain the clinical meaning of the alterations on brain metabolites concentration determined by 1H + MRS, 49 .…”

“…Into extracellular environment, NAA-G is hydrolyzed by glutamate-carboxipeptidase II, generating NAA, which diffuses into astrocytes, and the glutamate may be converted in glutamine, by the molecular incorporation of ammonia radical, under the action of glutamine-synthetase. NAA synthesized by neuronal mitochondria or derived from the dissociation of NAA-G, with the presence of an excess of brain nitrogen, is excreted by blood capillary of central nervous system, together with the excess of glutamine 49 (Fig 2).…”

A narrative review of sports-related concussion and return-to-play testing with asymptomatic athletes

“…20,24,25 It would seem that athletes who are back on the field with balance and body awareness insufficiencies could have a higher likelihood of other types of bodily injury, both of contact and noncontact etiology. The fMRI study from BMC Neurology showed that those involved in mTBI 6 months before testing had decreased N-acetylaspartate level in the M1 cortex, which has been implicated previous studies 11,22,23 as a marker for neuronal damage and mitochondrial dysfunction. These changes suggest that the effects of mTBI are persistent and may indicate irreversible damage.…”