Involvement of GAT2/BGT-1 in the preventive effects of betaine on cognitive impairment and brain oxidative stress in amyloid beta peptide-injected mice

摘要

In the pathophysiology of Alzheimer's disease (AD), the deposition of amyloid beta protein (A beta) is associated with oxidative stress, leading to cognitive impairment and neurodegeneration. Betaine (glycine betaine or trimethylglycine), known as an osmolyte and methyl donor in mammalian cells, has been reported to suppress the proinflammatory response and oxidative stress in the kidneys, but the effects of betaine on brain diseases remain to be determined. Here, to investigate the effects of betaine treatment on cognitive impairment and the increase in oxidative stress in the brain of an AD animal model, we performed a novel object recognition test and measured the malondialdehyde (MDA; a marker of oxidative stress) levels in the frontal cortex and hippocampus of mice intracerebroventricularly injected with A beta(25-35), an active fragment of A beta. Betaine prevented cognitive impairment as well as increases of the cortical and hippocampal MDA levels in A beta(25-35)-injected mice. Of note, NNC 05-2090, a selective inhibitor of betaine/GABA transporter-1 (GAT2/BGT-1), reduced the preventive effects of betaine on A beta(25-35)-induced cognitive impairment without affecting the increased MDA levels in the brain of A beta(25-35)-injected mice. As betaine is used as a substrate of GAT2/BGT-1, these results suggest that betaine is transported through GAT2/BGT-1 and prevents cognitive impairment in A beta(25-35)-injected mice, but GAT2/BGT-1 function is not required for the antioxidant effects of betaine.