Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington's disease mice

Bruce G. Jenkins, Peter Klivenyi, Ekkehard Kustermann, Ole A. Andreassen, Robert J. Ferrante, Bruce R. Rosen, M. Flint Beal

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

Mice transgenic for exon I of mutant huntingtin, with 141 CAG repeats, exhibit a profound symptomatology characterized by weight loss, motor disorders, and early death. We performed longitudinal analysis of metabolite levels in these mice using NMR spectroscopy in vivo and in vitro. These mice exhibited a large (53%), nonlinear drop in in vivo N-acetyl aspartate (NAA) levels over time, commencing at ~6 weeks of age, coincident with onset of symptoms. These drops in NAA levels occurred in the absence of neuronal death as measured by postmortem Nissl staining and neuronal counting but in the presence of nuclear inclusion bodies. In addition to decreased NAA, these mice showed a large elevation of glucose in the brain (600%) consistent with a diabetic profile and elevations in blood glucose levels both before and after glucose loading. In vitro NMR analysis revealed significant increases in glutamine (100%), taurine (95%) cholines (200%), and scyllo-inositol (333%) and decreases in glutamate (24%) and succinate (47%). These results lead to two conclusions. NAA is reflective of the health of neurons and thus is a noninvasive marker, with a temporal progression similar to nuclear inclusion bodies and symptoms, of neuronal dysfunction in transgenic mice. Second, the presence of elevated glutamine is evidence of a profound metabolic defect. We present arguments that the elevated glutamine results from a decrease in neuronal-glial glutamate-glutamine cycling and a decrease in glutaminase activity.

Original languageEnglish
Pages (from-to)2108-2119
Number of pages12
JournalJournal of neurochemistry
Volume74
Issue number5
DOIs
Publication statusPublished - May 3 2000

Keywords

  • Glucose
  • Glutamine
  • Huntington's disease transgenic mice
  • N-Acetyl aspartate
  • Spectroscopy

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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