In Vitro Expression of N‐Acetyl Aspartate by Oligodendrocytes

Abstract

Magnetic resonance spectroscopy (MRS) provides a noninvasive means of assessing in vivo tissue biochemistry. N-Acetyl aspartate (NAA) is a major brain metabolite, and its presence is used increasingly in clinical and experimental MRS studies as a putative neuronal marker. A reduction in NAA levels as assessed by in vivo 1 H MRS has been suggested to be indicative of neuronal viability. However, temporal observations of brain pathologies such as multiple sclerosis, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), and hypothyroidism have shown reversibility in NAA levels, possibly reflecting recovery of neuronal function. A knowledge of the cellular localisation of NAA is critical in interpreting these findings. The assumption that NAA is specific to neurones is based on previous immunohistochemical studies on whole brain using NAA-specific antibodies. The neuronal localisation was further substantiated by cell culture experiments in which its presence in the oligodendrocyte-type 2 astrocyte progenitors and immature oligodendrocytes, but not in the mature oligodendrocytes, was observed. More recently, studies on oligodendrocyte biology have revealed the requirement for trophic factors to promote the generation, maturation, and survival of oligodendrocytes in vitro. Here, we have used this new information to implement a more pertinent cell cultivation procedure and demonstrate that mature oligodendrocytes can express NAA in vitro. This observation brings into question whether the NAA changes observed in clinical in vivo 1 H MRS studies reflect neuronal function alone. The data presented here support the hypothesis that oligodendrocytes may express NAA in vivo and contribute to the NAA signal observed by 1 H MRS. Key Words: Oligodendrocyte-NAcetyl aspartate-Nuclear magnetic resonance-Cell metabolism-Brain development-Myelination.

High Resolution 1H NMR-based Metabolomics Indicates a Neurotransmitter Cycling Deficit in Cerebral Tissue from a Mouse Model of Batten Disease

“…Alternatively, we have shown previously the degradation of NAA to be slower in a mouse model of Cln8 (15). In addition, NAA is commonly thought of as a biomarker for neuronal density (44) and, as such, decreases have previously been linked to neuronal cell loss in numerous experimental and clinical conditions (45)(46)(47). Moreover, recent research has also suggested a role in cellular osmoregulation (35).…”

Severity of Fetal Brain Abnormalities in Congenital Heart Disease in Relation to the Main Expected Pattern of in utero Brain Blood Supply

“…Finally, from a technical point of view, we acknowledge that by using long TEs, the quantification of some metabolites with J-coupled spins (such as Ino and glutamate) is more challenging. However, long TEs provide clearer baselines and easier quantification, particularly of NAA [42]. …”

Proton Magnetic Resonance Spectroscopy Assessment of Fetal Brain Metabolism in Late-Onset ‘Small for Gestational Age' versus ‘Intrauterine Growth Restriction' Fetuses

“…During normative development, NAA/Cho levels steadily increase as the fetus grows to term [40,41]. Particularly, increasing NAA levels may reflect an increased myelination status associated with a growing synaptic complexity, with increased oligodendrocyte proliferation and differentiation [17,21,42] that is particularly intense during the third trimester of pregnancy. Lower mean NAA/Cho ratios in late IUGR and SGA fetuses could be attributable to either a delay in these normal maturational processes or to neuronal loss or injury [42,43].…”

“…This information on brain biochemistry is not available from standard fetal magnetic resonance imaging (MRI). In fetal brain spectra acquired with long echo times [16], the major observed metabolites are N-acetylaspartate (NAA) [17], a neuronal marker [18,19,20] although also localized in immature oligodendrocytes [15,21], total choline-containing compounds (mostly phosphocholine and glycerophosphocholine, Cho), which are essential for cell membrane turnover, and total creatine (creatine and phosphocreatine, Cr), which is present in both neurons and glia and essential for energy metabolism [15]. Since creatine levels are relatively unaffected by age or various pathologies, they are often used as a reference for quantification of other major metabolites in the form of ratios [22,23,24].…”