LETTER TO THE EDITOR
Chasing N‐acetyl‐L‐aspartate, a shiny NMR object in the brain
N‐acetyl‐L‐aspartate (NAA) is an important NMR object in the mammalian brain almost exclusively present in neurons. It is the most concentrated
acetylated amino acid in human brain, at about 10mM, and one of the most concentrated amino acids present in neurons, at about 20mM. NAA has
a strong proton MRS signature, at about 2.02 ppm, and is considered to be a specific marker for neuron density and/or viability and an indicator of
neuronal loss in many human‐brain pathologies. The “NAA' signal is used as a reference point in most brain MRS studies, and its ratio to other brain
metabolites, many of which are present in different cells, indicates focal or global brain health in many medical conditions.
NAA's high concentration in brain has prompted a search for its function. In 2000, its unique tricellular metabolism was documented.
neurons, NAA is synthesized via NAA synthase
from acetyl coenzyme A, derived from the oxidation of glucose (Glc), and L‐aspartate (Asp). The
dipeptide N‐acetylaspartylglutamate (NAAG) is then synthesized from NAA and L‐glutamate (Glu) via NAAG synthase
; this is the only known
pathway for NAAG synthesis. Both NAA and NAAG turn over every 14 to16 hours, but, remarkably, neither substance can be catabolized by
neurons. NAAG is released into extracellular fluid (ECF) and targeted to astrocytes, where it docks with the metabotropic Glu receptor 3 (mGluR3)
and is cleaved into Glu and NAA by NAAG peptidase.
Astrocytes cannot hydrolyze NAA, so it is released into ECF, taken up by oligodendrocytes,
and cleaved into acetate and Asp by aspartoacylase (ASPA),
and its products are completely metabolized.
While the biochemical pathways in the
tricellular metabolism of NAA were already clear, its function and the specific physiological roles of cells in this sequence were not. In Figure 1, the
biochemical and metabolic relationships of cells in the tricellular sequence are graphically illustrated.
The purpose of this letter is to bring attention to the complex and dynamic nature of these substances and point out that, in many brain dis-
orders, associations have been found between NAAG, astrocyte NAAG peptidase, and the NAAG‐targeted mGluR3 receptor, but not with NAA.
The only metabolic purpose of intra‐neural NAA is to synthesize NAAG, and the apparent role of NAAG is to act as a neurotransmitter. It is targeted
to the mGluR3, a receptor type prominent on the astrocyte surface, where it is hydrolyzed by astrocyte‐expressed NAAG peptidase to liberate Glu,
a key component in neurovascular coupling (NVC). However, because of the abundance and relative ease of measurement of NAA, correlations
with other brain metabolites and/or regional differences between healthy brains versus those exhibiting various disorders have usually been made
with NAA, a non‐neurotransmitter, rather than with the neurotransmitter NAAG.
Focusing on NAA may have diverted attention from what appears to be an important function of the tricellular sequence: the production,
release, and subsequent catabolism of NAAG in gray matter (GM) and white matter (WM).
In GM, NAAG is present at low concentrations; in
WM, at much higher concentrations, and with an NMR peak at about 2.04 ppm, it is not easily separated from NAA. Because of this, many studies
report NAA and NAAG as total NAA (tNAA), even though the ratio of the two is known to be very different in different brain regions. In humans,
tNAA is nearly constant in most brain regions but the NAA/NAAG ratio varies. In parietal WM, NAAG was reported as 21.4% of the tNAA concen-
tration, and in parietal GM it could not be detected using MRS.
In rat brains using high‐pressure liquid chromatography, regional tNAA was found
to be fairly constant, but NAAG as a percentage of tNAA content varied greatly: in the visual cortex, motor cortex, cerebellum, brainstem, and optic
nerve, NAAG was 1.93, 2.35, 5.46, 16.19, and 60.29% of tNAA content respectively.
Analytical methods have been used to isolate the NAA MRS
signal, but in these analyses, the intracellular content of NAA tied up in NAAG is not included. However, specific MRS methods that separated NAA
signals from NAAG signals revealed an important step in understanding the function of NAA: in a dynamic study of the human visual cortex, at a
magnetic field strength of 3 T and using a MEGA‐PRESS spectral editing sequence, it was found that upon stimulation within minutes the NAA
signal was reduced by about 21% and the NAAG signal rose by about 64%, values representing a close millimolar equivalence between NAA loss
and NAAG increase.
Recovery of both to pre‐stimulation levels also occurred within minutes, and since NAAG cannot be catabolized by neurons,
it had to have been released and catabolized by juxtaposed astrocytes. Most MRS studies performed are steady state, so this dynamic study
established for the first time that rapid stimulation‐induced NAAG production was an important function of intra‐neural NAA, although the
physiological role of released NAAG remained obscure. In this regard, the following findings are of interest.
First, a bimodal nature of NVC for supply of energy has been observed,
a slow tonic non‐synaptic NVC mechanism without astrocyte Ca
signaling operating on capillaries over tens of seconds, and a rapid phasic synaptic Glu‐released NVC where astrocyte Ca
signaling is involved and
both arteriole and capillary responses occur in 2‐3 s. In this study it was estimated that the tonic mode accounted for about 50% of NVC. The
tricellular NAA sequence is a neuronal signaling system aimed at astrocytes—the key cellular component in NVC—and NAAG is a neurotransmitter
directly connected to the rate of neuron Glc metabolism. Thus, the rate of synthesis and release of NAAG to the astrocyte mGluR3 indicates a
neuron's level of metabolic activity and its ongoing energy requirements. Evidence that NAAG is the neurotransmitter regulating tonic NVC in both
GM and WM has been presented.
This evidence, while compelling, does not preclude NAA and NAAG from having other functions in brain as well,
Received: 12 November 2017 Revised: 15 December 2017 Accepted: 18 December 2017
NMR in Biomedicine. 2018;31:e3895.
Copyright © 2018 John Wiley & Sons, Ltd.wileyonlinelibrary.com/journal/nbm 1of3