Background: The deposition of amyloid-β (Aβ) and hyperphosphorylation of tau are well-known as the pathophysiological features of Alzheimer’s disease (AD), leading to oxidative stress and synaptic deficits followed by cognitive symptoms. We already demonstrated that betaine (glycine betaine) prevented cognitive impairment and hippocampal oxidative stress in mice intracerebroventricularly injected with an active fragment of Aβ, whereas the effect of betaine in chronic models of AD remains unknown. Objective: Our objective was to investigate the effects of chronic betaine intake on cognitive impairment and aberrant expression of genes involved in synapse and antioxidant activity in the hippocampus of a genetic AD model. Methods: We performed cognitive tests and RT-PCR in the hippocampus in 3xTg mice, a genetic AD model. Results: Cognitive impairment in the Y-maze and novel object recognition tests became evident in 3xTg mice at 9 months old, and not earlier, indicating that cognitive impairment in 3xTg mice developed age-dependently. To examine the preventive effect of betaine on such cognitive impairment, 3xTg mice were fed betaine-containing water for 3 months from 6 to 9 months old, and subsequently subjected to behavioral tests, in which betaine intake prevented the development of cognitive impairment in 3xTg mice. Additionally, the expression levels of genes involved in synapse and antioxidant activity were downregulated in hippocampus of 3xTg mice at 9 months old compared with age-matched wild-type mice, which were suppressed by betaine intake. Conclusion: Betaine may be applicable as an agent preventing the progression of AD by improving the synaptic structure/function and/or antioxidant activity.

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