Low glycine levels in brain homogenates of TgSwDI mice compared to wild-type mice

Abstract

Background: In Alzheimer’s disease (AD), accumulation of amyloid b (Ab) protein can disturb normal glutamatergic neurotransmission. Glutamate is an important neurotransmitter in learning and memory but, when present in high amounts, can also be excitotoxic, resulting in neuronal loss. Indeed, the loss of glutamatergic neurons can be linked to the cognitive impairments seen in AD patients. As disturbances in the glutamatergic system are closely linked to AD, it is our aim to search for potential biomarkers of the glutamatergic system. To this end, we characterized levels of glutamate-related metabolites in the TgSwDI mouse model for AD. Methods: Male and female TgSwDI mice with mild (3 months old) and severe (9 months old) Ab pathology and non-transgenic (C57Bl/6) age-matched controls, were sacrificed by cervical dislocation. Afterwards, their brains were dissected into different brain regions (i.e. hippocampus, cortex) and snapfrozen until analysis. Distilled water was used to dissolve metabolites from tissue. Using an amino acid analyzer, concentrations of various glutamate-related amino acids (i.e. glutamate, glutamine, GABA, glycine, aspartate, asparagine, alanine) were determined. Results: Glutamate levels were hardly changed in TgSwDI mice. However, a consistent significant decrease in glycine concentration was observed in TgSwDI mice compared to agematched non-transgenic mice, independent of age, sex or the brain area tested. Furthermore, in most of the brain samples, aspartate levels were also (significantly) decreased. Levels of other amino acids were unaltered or inconsistently changed in the various brain areas. Conclusions: In TgSwDI mice, glutamate levels remain unchanged, but brain glycine levels, and to a lesser extent aspartate levels, are decreased. This result suggests that these metabolites may be candidate biomarkers reflecting disturbances in glutamatergic neurotransmission.