Normalization of hyperhomocysteinemia improves cognitive deficits and ameliorates brain amyloidosis of a transgenic mouse model of Alzheimer's disease.

Hyperhomocysteine (HHcy) is a risk factor for developing Alzheimer's disease (AD). Previously, we showed that diet-induced HHcy accelerated the AD-like phenotype of a transgenic mouse model, i.e., Tg2576. In the present work, we tested whether an HHcy-lowering strategy in this model would be beneficial. Tg2576 mice received methionine-rich or regular chow diet for 5 mo. Next, while the chow control group was kept on the same regimen, the other mice were randomized into two groups: one was kept on the methionine-rich diet (Met On), the other switched to chow (Met Off). Compared with controls, 5 mo on the methionine-rich diet resulted in HHcy (plasma Hcy level, treated: 12.7±1.2 μM vs. control: 3.1±0.4 μM) and significant behavioral impairments (% freezing, treated: 2.4±1.4% vs. control: 19.9±6.9%). At the end of the study, while the Met On group kept Hcy level elevated, the Met Off group had these values indistinguishable from the controls. The reduction in Hcy levels resulted in a significant improvement of the fear-conditioning performance, and an amelioration of the brain amyloidosis. Our results demonstrate that lowering HHcy in a transgenic AD-mouse model is beneficial since it significantly improves behavior deficits and brain amyloidosis. Our findings provide new biological insights for future clinical trials aimed at lowering this modifiable risk factor in human AD.