Department of Pathophysiology, Key Laboratory of Neurological Disease of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Alzheimers Dis. 2011;27(3):639-50. doi: 10.3233/JAD-2011-110770.
Hyperhomocysteinemia is associated with an increased risk of Alzheimer's disease (AD). Our previous work has demonstrated that combined folate and vitamin B12 (vit-B12) supplementation prevents tau hyperphosphorylation and memory deficits induced by acute administration of homocysteine in young rats. Here, we further investigated whether folate/vit-B12 supplementation is also effective in aged rats with a chronically high level of homocysteine. 18-month-old rats were injected with homocysteine via the vena caudalis with or without a concurrent folate/vit-B12 supplementation for 28 weeks. We found that hyperhomocysteinemia induced tau hyperphosphorylation and accumulation in hippocampus and cortex. Concurrent signaling changes included the activation of glycogen synthase kinases-3β, cyclin-dependent kinase-5, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38MAPK, and inhibition of protein phosphatase 2A. Although the ability to learn was not affected, the aged rats exhibited significant memory deficits. Folate/vit-B12 supplementation attenuated these biochemical and behavioral correlates. These data demonstrate that folate/vit-B12 supplementation is also effective in a chronic hyperhomocysteinemia model in reversing the AD-like tau pathologies and memory deficits.
高同型半胱氨酸血症与阿尔茨海默病（AD）风险增加有关。我们之前的工作表明，叶酸和维生素 B12（vit-B12）联合补充可预防同型半胱氨酸急性给药诱导的年轻大鼠 tau 过度磷酸化和记忆缺陷。在这里，我们进一步研究了叶酸/vit-B12 补充是否也对同型半胱氨酸水平持续升高的老年大鼠有效。18 个月大的大鼠通过尾静脉注射同型半胱氨酸，或同时给予叶酸/vit-B12 补充 28 周。我们发现高同型半胱氨酸血症诱导海马和皮质中的 tau 过度磷酸化和积累。同时发生的信号变化包括糖原合酶激酶-3β、周期蛋白依赖性激酶-5、c-Jun N 末端激酶、细胞外信号调节激酶和 p38MAPK 的激活，以及蛋白磷酸酶 2A 的抑制。尽管学习能力不受影响，但老年大鼠表现出明显的记忆缺陷。叶酸/vit-B12 补充可减轻这些生化和行为相关性。这些数据表明，叶酸/vit-B12 补充在逆转 AD 样 tau 病理学和记忆缺陷方面在慢性高同型半胱氨酸血症模型中也有效。
