Pacheco-Quinto Javier, Rodriguez de Turco Elena B, DeRosa Steven, Howard Altovise, Cruz-Sanchez Felix, Sambamurti Kumar, Refolo Lorenzo, Petanceska Suzana, Pappolla Miguel A
Neuroscience Center of Excellence, LSU Health Science Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA.
Neurobiol Dis. 2006 Jun;22(3):651-6. doi: 10.1016/j.nbd.2006.01.005. Epub 2006 Mar 3.
Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (Abeta) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBS(tm1Unc) mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of Abeta40 and Abeta42 levels in the brain. Correlations between homocysteine levels in serum and brain Abeta levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found. The causes of neuronal dysfunction and degeneration in AD are not fully understood, but increased production of Abeta seems to be of major importance. By unveiling a link between homocysteine and Abeta levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD.
近期的流行病学和临床数据表明，血清同型半胱氨酸水平升高可能会增加患阿尔茨海默病（AD）的风险，但其潜在机制尚不清楚。我们检验了以下假设：高血清同型半胱氨酸浓度可能会增加大脑中β淀粉样肽（Aβ）的水平，从而加速AD神经病理学进程。为此，我们将携带胱硫醚-β-合酶（CBS*）杂合显性突变的高同型半胱氨酸血症CBS(tm1Unc)小鼠与脑淀粉样变性的APP*/PS1小鼠模型进行交配。与淀粉样变性的双转基因APP/PS1模型相比，APP/PS1*/CBS小鼠的血清同型半胱氨酸水平显著升高。结果显示，雌性（而非雄性）APP/PS1*/CBS*小鼠大脑中的Aβ40和Aβ42水平显著升高。血清同型半胱氨酸水平与脑Aβ水平之间的相关性具有统计学意义。在高同型半胱氨酸血症小鼠中未发现β分泌酶活性增加或神经元细胞丢失的证据。AD中神经元功能障碍和变性的原因尚未完全了解，但Aβ生成增加似乎至关重要。通过揭示同型半胱氨酸与Aβ水平之间的联系，这些发现推进了我们对高同型半胱氨酸血症作为AD危险因素所涉及机制的理解。
