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Short-Term Cuprizone Feeding Verifies N-Acetylaspartate Quantification as a Marker of Neurodegeneration

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Abstract

Proton magnetic resonance spectroscopy (1H-MRS) is a quantitative MR imaging technique often used to complement conventional MR imaging with specific metabolic information. A key metabolite is the amino acid derivative N-Acetylaspartate (NAA) which is an accepted marker to measure the extent of neurodegeneration in multiple sclerosis (MS) patients. NAA is catabolized by the enzyme aspartoacylase (ASPA) which is predominantly expressed in oligodendrocytes. Since the formation of MS lesions is paralleled by oligodendrocyte loss, NAA might accumulate in the brain, and therefore, the extent of neurodegeneration might be underestimated. In the present study, we used the well-characterized cuprizone model. There, the loss of oligodendrocytes is paralleled by a reduction in ASPA expression and activity as demonstrated by genome-wide gene expression analysis and enzymatic activity assays. Notably, brain levels of NAA were not increased as determined by gas chromatography–mass spectrometry and 1H-MRS. These important findings underpin the reliability of NAA quantification as a valid marker for the paraclinical determination of the extent of neurodegeneration, even under conditions of oligodendrocyte loss in which impaired metabolization of NAA is expected. Future studies have to reveal whether other enzymes are able to metabolize NAA or whether an excess of NAA is cleared by other mechanisms rather than enzymatic metabolism.

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Abbreviations

1H-MRS:

Proton magnetic resonance spectroscopy

APC:

Adenomatous polyposis coli protein

APP:

Anti-amyloid precursor protein

ASPA:

Aspartoacylase

CC:

Corpus callosum

CNS:

Central nervous system

CD:

Canavan disease

Co:

Control

Cuprizone:

bis-Cyclohexanone oxaldihydrazone

GC/MS:

Gas chromatography–mass spectrometry

GFAP:

Glial fibrillary acid protein

GM:

Gray matter

H.E.:

Haematoxylin–eosin

HPRT:

Hypoxanthin guanine phosphoribosyltransferase

IBA1:

Ionized calcium binding adaptor molecule 1

IHC:

Immunohistochemistry

LFB:

Luxol Fast Blue

MR:

Magnetic resonance

MS:

Multiple sclerosis

MRI:

Conventional magnetic resonance imaging

NAA:

N-Acetylaspartate

NAWM:

Normal-appearing white matter

NAGM:

Normal-appearing grey matter

PAS:

Periodic Acid Schiff

Real-time RT-PCR:

Real-time reverse transcriptase-polymerase chain reaction

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Acknowledgments

We would like to thank Helga Helten, Petra Ibold and Wouter Gerritsen for excellent technical assistance. This study was supported by a grant from ProMyelo - SFZ

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Authors and Affiliations

  1. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany

    Barbara Maria Krauspe, Cordian Beyer, Katharina Janssen, Tim Clarner & Markus Kipp

  2. Department of Chemistry, in-vivo-MR, University of Bremen, Bremen, Germany

    Wolfgang Dreher

  3. Institute of Biomedical Mechatronics, Johannes Kepler University Linz, Linz, Austria

    Werner Baumgartner

  4. Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University, Aachen, Germany

    Bernd Denecke

  5. Department of General Pediatrics, Division of Inherited Metabolic Disease, University Children’s Hospital Heidelberg, 69120, Heidelberg, Germany

    Claus-Dieter Langhans

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  1. Barbara Maria Krauspe
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  2. Wolfgang Dreher
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  8. Tim Clarner
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  9. Markus Kipp
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Correspondence to Markus Kipp.

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Krauspe, B.M., Dreher, W., Beyer, C. et al. Short-Term Cuprizone Feeding Verifies N-Acetylaspartate Quantification as a Marker of Neurodegeneration. J Mol Neurosci 55, 733–748 (2015). https://doi.org/10.1007/s12031-014-0412-6

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