Skip to main content
Log in

Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain’s “operating system”: how NAA metabolism supports meaningful intercellular frequency-encoded communications

  • Minireview Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

N-acetylaspartate (NAA), an acetylated derivative of l-aspartate (Asp), and N-acetylaspartylglutamate (NAAG), a derivative of NAA and l-glutamate (Glu), are synthesized by neurons in brain. However, neurons cannot catabolize either of these substances, and so their metabolism requires the participation of two other cell types. Neurons release both NAA and NAAG to extra-cellular fluid (ECF) upon stimulation, where astrocytes, the target cells for NAAG, hydrolyze it releasing NAA back into ECF, and oligodendrocytes, the target cells for NAA, hydrolyze it releasing Asp to ECF for recycling to neurons. This sequence is unique as it is the only known amino acid metabolic cycle in brain that requires three cell types for its completion. The results of this cycling are two-fold. First, neuronal metabolic water is transported to ECF for its removal from brain. Second, the rate of neuronal activity is coupled with focal hyperemia, providing stimulated neurons with the energy required for transmission of meaningful frequency-encoded messages. In this paper, it is proposed that the tri-cellular metabolism of NAA functions as the “operating system” of the brain, and is essential for normal cognitive and motor activities. Evidence in support of this hypothesis is provided by the outcomes of two human inborn errors in NAA metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

Ac:

Acetate

AcCoA:

Acetyl coenzyme A

Asp:

Aspartate

APQ4:

Aquaporin 4

ASPA:

Aspartoacylase

BBB:

Blood brain barrier

ECF:

Extracellular fluid

fMRI:

Functional magnetic resonance imaging

fMRS:

Functional magnetic resonance spectroscopy

Glc:

Glucose

Gln:

Glutamine

Glu:

Glutamate

GRM3:

Metabotropic Glu receptor 3

MWP:

Molecular water pump

NAA:

N-acetylaspartate

NAAG:

N-acetylaspartylglutamate

References

  • Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, Engel A, Neilsen S (2002) Aquaporin water channels-from atomic structure to clinical medicine. J Physiol 542:3–16

    Article  CAS  PubMed  Google Scholar 

  • Andrew RD, Labron MW, Boehnke SE, Carnduff L, Kirov SA (2007) Physiological evidence that pyramidal neurons lack functional water channels. Cereb Cortex 17:787–802

    Article  PubMed  Google Scholar 

  • Baslow MH (1999) The existence of molecular water pumps in the nervous system. A review of the evidence. Neurochem Int 34:77–90

    Article  CAS  PubMed  Google Scholar 

  • Baslow MH (2000) Functions of N-acetyl-l-aspartate and N-acetyl-l-aspartylglutamate in the vertebrate brain. Role in glial cell-specific signaling. J Neurochem 75:453–459

    Article  CAS  PubMed  Google Scholar 

  • Baslow MH (2006) NAAG peptidase as a therapeutic target: Potential for regulating the link between glucose metabolism and cognition. Drug News Perspect 19(3):145–150

    Article  CAS  PubMed  Google Scholar 

  • Baslow MH (2007) N-Acetylaspartate and N-acetylaspartylglutamate, Chap 14. In: Lajtha A (ed) Handbook of neurochemistry and molecular neurobiology, vol 6, 3rd edn, Amino acids and peptides in the nervous system, pp 418, Springer Science, New York, pp 305–346

    Google Scholar 

  • Baslow MH (2008) The astrocyte surface NAAG receptor and NAAG peptidase signaling complex as a therapeutic target. Drug News Perspect 21(5):251–257

    Article  CAS  PubMed  Google Scholar 

  • Baslow MH (2009a) A novel key-lock mechanism for inactivating amino acid neurotransmitters during transit across extracellular space. Amino Acids (doi10.1007/s00726-009-0232-0)

  • Baslow MH (2009b) The languages of neurons; an analysis of coding mechanisms by which neurons communicate, learn and store information. Entropy 11(4):782–797

    Article  Google Scholar 

  • Baslow MH, Guilfoyle DN (2007) Using proton magnetic resonance imaging and spectroscopy to understand brain “activation”. Brain Lang 102(2):153–164

    Article  PubMed  Google Scholar 

  • Baslow MH, Guilfoyle DN (2009) Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease? Neurochem Res 34(9):1523–1534

    Article  CAS  PubMed  Google Scholar 

  • Bitto E, Bingman CA, Wesenberg GE et al (2007) Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. PNAS 104(2):456–461

    Article  CAS  PubMed  Google Scholar 

  • Boltshauser E, Schmitt B, Wevers RA, Engelke U, Burlina AB, Burlina AP (2004) Follow-up of a child with hypoacetylaspartia. Neuropediatrics 35(4):255–258

    Article  CAS  PubMed  Google Scholar 

  • Buffoli B (2010) Aquaporin biology and nervous system. Curr Neuropharmacol 8:97–104

    Article  Google Scholar 

  • Curatolo A, D’Archangelo P, Lino A, Brancati A (1965) Distribution of N-acetylaspartic and N-acetylaspartylglutamic acids in nervous tissue. J Neurochem 12:339–342

    Article  CAS  PubMed  Google Scholar 

  • Martin E, Capone A, Schneider J, Hennig J, Thiel T (2001) Absence of N-acetylaspartate in the human brain: impact on neurospectroscopy? Ann Neurol 49:518–521

    Article  CAS  PubMed  Google Scholar 

  • Matalon R, Michals K, Sebasta D, Deanching M, Gashkoff P, Casanova J (1988) Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 29:463–471

    Article  CAS  PubMed  Google Scholar 

  • Meinild A-K, Klaerke DA, Loo DDF, Wright EM, Zeuthen T (1998) The human Na+-glucose cotransporter is a molecular water pump. J Physiol 508(1):l5–21

    Google Scholar 

  • Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM (2007) N-acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81:89–131

    Article  CAS  PubMed  Google Scholar 

  • Rash JE, Duffy HS, Dudek FE, Bilhartz BL, Whalen LR, Yasumura T (1997) Grid-mapped freeze-fracture analysis of gap junctions in gray and white matter of adult rat central nervous system, with evidence for a “panglial syncytium” that is not coupled to neurons. J Comp Neurol 388(2):265–292

    Article  CAS  PubMed  Google Scholar 

  • Smith AJ, Blumenfeld H, Behar KL, Rothman DL, Shulman RG, Hyder F (2002) Cerebral energetics and spiking frequency: the neurophysiological basis of fMRI. Proc Natl Acad Sci USA 99:10765–10770

    Article  CAS  PubMed  Google Scholar 

  • Tallan HH, Moore S, Stein WH (1954) Studies on the free amino acids and related compounds in tissues of the cat. J Biol Chem 211:927–939

    CAS  PubMed  Google Scholar 

  • Tallan HH, Moore S, Stein WH (1956) N-acetyl-l-aspartic acid in brain. J Biol Chem 219:257–264

    CAS  PubMed  Google Scholar 

  • Wiame E, Tyteca D, Pierrot N, Collard F, Amyere M, Noel G, Desmedt J et al (2010) Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia. Biochem J 425:127–136

    Article  CAS  Google Scholar 

Download references

Conflict of interest statement

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Morris H. Baslow.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Baslow, M.H. Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain’s “operating system”: how NAA metabolism supports meaningful intercellular frequency-encoded communications. Amino Acids 39, 1139–1145 (2010). https://doi.org/10.1007/s00726-010-0656-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-010-0656-6

Keywords

Navigation