Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer's disease: a 13C NMR study.
Alzheimer's disease is an age-related neurodegenerative disease characterized by deterioration of cognition and loss of memory. Several clinical studies have shown Alzheimer's disease to be associated with disturbances in glucose metabolism and the subsequent tricarboxylic acid (TCA) cycle-related metabolites like glutamate (Glu), glutamine (Gln), and N-acetylaspartate (NAA). These metabolites have been viewed as biomarkers by (a) assisting early diagnosis of Alzheimer's disease and (b) evaluating the efficacy of a treatment regimen. In this study, 13-month-old triple transgenic mice (a mouse model of Alzheimer's disease (3xTg-AD)) were given intravenous infusion of [1-(13)C]glucose followed by an ex vivo (13)C NMR to determine the concentrations of (13)C-labeled isotopomers of Glu, Gln, aspartate (Asp), GABA, myo-inositol, and NAA. Total ((12)C+(13)C) Glu, Gln, and Asp were quantified by high-performance liquid chromatography to calculate enrichment. Furthermore, we examined the effects of lipoic acid in modulating these metabolites, based on its previously established insulin mimetic effects. Total (13)C labeling and percent enrichment decreased by ∼50% in the 3xTg-AD mice. This hypometabolism was partially or completely restored by lipoic acid feeding. The ability of lipoic acid to restore glucose metabolism and subsequent TCA cycle-related metabolites further substantiates its role in overcoming the hypometabolic state inherent in early stages of Alzheimer's disease.
Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
Harsh
H
Sancheti
Enhanced Magnetic Resonance Laboratory, Huntington Medical Research Institutes, Pasadena, California, USA.
Keiko
K
Kanamori
Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
Ishan
I
Patil
Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
Roberta
R
Díaz Brinton
Enhanced Magnetic Resonance Laboratory, Huntington Medical Research Institutes, Pasadena, California, USA.
Brian D
BD
Ross
Pharmacology & Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
Enrique
E
Cadenas
D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002952:Citric Acid Cycle / Q000187:drug effects* / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000097:blood / Q000235:genetics; D005973:Glutamine / Q000097:blood / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008063:Thioctic Acid / Q000494:pharmacology*; D014803:Vitamin B Complex / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000097:blood / Q000235:genetics
D015415:Biomarkers; D005973:Glutamine; D014803:Vitamin B Complex; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D008063:Thioctic Acid; C000179:N-acetylaspartate; D005947:Glucose