Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, UMass Lowell, Lowell, MA 01821, USA.
J Alzheimers Dis. 2012;28(2):423-31. doi: 10.3233/JAD-2011-111025.
S-adenosyl methionine (SAM) contributes to multiple pathways in neuronal homeostasis, several of which are compromised in age-related neurodegeneration and Alzheimer's disease. Dietary supplementation of transgenic mice with SAM maintained acetylcholine levels, cognitive performance, oxidative buffering capacity, and phosphatase activity, and reduced aggression, calcium influx, endogenous PS-1 expression, γ-secretase activity, and levels of amyloid-β (Aβ) and phospho-tau. Herein, we examined whether or not SAM could delay neuropathology in 3xTg-AD mice, which harbor mutant genes for human AβPP, PS-1 and tau. Mice received a standard AIN-76 diet with or without SAM (100 mg/kg diet) for 1 month commencing at 10 months of age or for 3 months commencing at 12.5 months of age; mice were sacrificed and examined for Aβ and tau neuropathology at 11 and 15.5 months of age, respectively. SAM supplementation reduced hippocampal intracellular AβPP/Aβ and phospho-tau immunoreactivity to a similar extent at both sampling intervals. Supplementation reduced the number of extracellular Aβ deposits by 80% (p < 0.01) at 11 months of age after 1 month of treatment but only by 24% (p < 0.34) at 15.5 months of age after 3 months of treatment. As anticipated, neurofibrillary tangles were not observed in mice at these young ages; however, supplementation reduced levels of phospho-tau and caspase-cleaved tau within Sarkosyl-insoluble preparations in mice at 15.5 months of age. These limited analyses indicate that SAM can modulate the time course of AD neuropathology, and support further long-term analyses.
S-腺苷甲硫氨酸（SAM）有助于神经元动态平衡的多种途径，其中一些在与年龄相关的神经退行性变和阿尔茨海默病中受到损害。用 SAM 对转基因小鼠进行饮食补充，可维持乙酰胆碱水平、认知表现、氧化缓冲能力和磷酸酶活性，并降低攻击性、钙内流、内源性 PS-1 表达、γ-分泌酶活性以及淀粉样蛋白-β（Aβ）和磷酸化 tau 的水平。在此，我们研究了 SAM 是否可以延缓携带人 AβPP、PS-1 和 tau 突变基因的 3xTg-AD 小鼠的神经病理学进展。从 10 个月大开始，小鼠接受标准 AIN-76 饮食或含有 SAM（100mg/kg 饮食）的饮食 1 个月，或从 12.5 个月大开始接受 SAM 补充 3 个月；在 11 个月和 15.5 个月大时，分别对小鼠进行 Aβ 和 tau 神经病理学检查。SAM 补充治疗在两个采样间隔均可使海马细胞内 AβPP/Aβ 和磷酸化 tau 免疫反应性降低到相似程度。补充治疗在 1 个月的治疗后 11 个月可使细胞外 Aβ 沉积数量减少 80%（p < 0.01），但在 3 个月的治疗后 15.5 个月仅减少 24%（p < 0.34）。如预期的那样，在这些年轻的小鼠中未观察到神经原纤维缠结；然而，补充治疗可降低 15.5 个月大的小鼠 Sarkosyl 不溶性制剂中磷酸化 tau 和 caspase 切割 tau 的水平。这些有限的分析表明，SAM 可以调节 AD 神经病理学的时间进程，并支持进一步的长期分析。
