The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus.
The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus.
复制标题
DOI：
10.1523/jneurosci.2775-12.2012
复制
发表时间：
2012-11-14
期刊：
影响因子：
--
通讯作者：
Checler F
中科院分区：
文献类型：
--
作者：
Lauritzen I;Pardossi-Piquard R;Bauer C;Brigham E;Abraham JD;Ranaldi S;Fraser P;St-George-Hyslop P;Le Thuc O;Espin V;Chami L;Dunys J;Checler F
过度表达瑞典突变 β-amyloiḍprecursoṛ蛋白 (βAPPswe)、P310L-Tau (TauP301L) 和生理水平的 M146V-presenilin-1 (PS1M146V) 的三重转基因小鼠 (3xTgAD) 显示细胞外淀粉样蛋白 -β 肽 (Aβ) 沉积物和 Tau 缠结。更有争议的是，这些小鼠的神经元内 Aβ 积累与突触功能障碍和认知缺陷有关。在这里，我们提供了 β-分泌酶衍生的 βAPP 片段 C99 的早期、年龄依赖性和海马特异性积累的免疫组织学、遗传和药理学证据，这种积累在 3 个月大的小鼠中观察到，并通过 γ-分泌酶的药理学阻断而增强。值得注意的是，细胞内 Aβ 仅在几个月后才可检测到，并且与 C99 一样，出现在增大的组织蛋白酶 B 阳性结构中，而细胞外 Aβ 沉积物在 12 个月龄左右及以后才检测到。早期 C99 的产生主要发生在海马的 CA1/皮下交汇区，对应于老年小鼠中第一个出现斑块和缠结的区域。对另外两种携带突变 βAPP 但内源性野生型 PS1 和 Tau 蛋白（TgCRND8 或 Tg2576）的小鼠模型的检查表明，所有动物模型中的 C99 水平均远高于各自的对照小鼠。此外，将 3xTgAD 小鼠与携带 βAPPswe 和 TauP301L 突变但表达内源 PS1 (2xTgAD) 的双转基因小鼠进行比较表明，C99 积累不能用 PS1 突变触发的功能丧失来解释，PS1 突变可能会阻止 γ-分泌酶对 C99 的二次裂解。总之，我们的工作确定 C99 是最早的 βAPP 分解代谢物，也是 3xTgAD 小鼠细胞内 βAPP 相关免疫反应性的主要贡献者，表明它是该小鼠模型中发生的神经退行性过程和认知改变的启动子。
Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated β-amyloiḍprecursoṛprotein (βAPPswe), P310L-Tau (TauP301L) and physiological levels of M146V-presenilin-1 (PS1M146V) display extracellular amyloid-β peptides (Aβ) deposits and Tau tangles. More disputed is the observation that these mice accumulate intraneuronal Aβ that has been linked to synaptic dysfunction and cognitive deficits. Here, we provide immunohistological, genetic and pharmacological evidences for early, age-dependent and hippocampus-specific accumulation of the β-secretase-derived βAPP fragment C99 that is observed in 3 month-old mice and enhanced by pharmacological blockade of γ-secretase. Notably, intracellular Aβ is only detectable several months later and appears, as is the case for C99, in enlarged cathepsin B-positive structures, while extracellular Aβ deposits are detected around 12 months of age and beyond. Early C99 production occurs mainly in the CA1/subicular interchange area of the hippocampus corresponding to the first region exhibiting plaques and tangles in old mice. The examination of two other mice models harboring mutated βAPP but endogenous wild type PS1 and Tau protein (TgCRND8 or Tg2576) indicate that C99 levels are largely higher in all animal models than in their respective control mice. Furthermore, the comparison of 3xTgAD mice with double transgenic mice bearing the βAPPswe and TauP301L mutations but expressing endogenous PS1 (2xTgAD) demonstrate that C99 accumulation could not be accounted for by a loss of function triggered by PS1 mutation that would have prevented C99 secondary cleavage by γ-secretase. Altogether, our work identifies C99 as the earliest βAPP catabolite and main contributor to the intracellular βAPP-related immunoreactivity in 3xTgAD mice, suggesting its implication as an initiator of the neurodegenerative process and cognitive alterations taking place in this mice model.