Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase.
Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase.
复制标题
DOI：
--
复制
发表时间：
2004
影响因子：
3.5
通讯作者：
J. Jankowsky;Daniel J. Fadale;Jeffrey Anderson;Guilian Xu;V. Gonzales;N. Jenkins;N. Copeland;
中科院分区：
文献类型：
--
作者：
J. Jankowsky;Daniel J. Fadale;Jeffrey Anderson;Guilian Xu;V. Gonzales;N. Jenkins;N. Copeland;
淀粉样前体蛋白（APP）被β - 分泌酶1（BACE1）和γ - 分泌酶进行内切蛋白水解加工，释放出淀粉样肽（Aβ40和Aβ42），这些肽在阿尔茨海默病（AD）患者的大脑中聚集形成老年斑。Aβ40/42的C末端是由γ - 分泌酶产生的，其活性依赖于早老素（PS1或PS2）。早发性家族性阿尔茨海默病（FAD）患者存在PS1（和PS2）的错义突变，先前在转基因小鼠和培养细胞模型中的研究表明，FAD - PS1变体改变了Aβ40∶Aβ42的比例，使Aβ42增多。解释这一结果的一个假设是突变的PS改变了γ - 分泌酶的特异性，使得以Aβ40为代价更有利于Aβ42的产生。为了在体内验证这一假设，我们研究了一系列转基因小鼠中Aβ40和Aβ42的水平，这些小鼠共同表达APP的瑞典突变体（APPswe）以及两种在大脑中对淀粉样病变有不同加速作用的FAD - PS1变体。我们证明了Aβ42的浓度与淀粉样沉积的速率之间存在直接相关性。我们进一步表明，与FAD - PS1变体表达相关的Aβ42∶Aβ40比例的改变是由于Aβ42的稳态水平特异性升高，而Aβ40的水平保持不变。这些数据表明，PS1变体不仅仅是改变了γ - 分泌酶的首选切割位点，而是对γ - 分泌酶的调节及其对底物的获取具有更复杂的影响。
Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and gamma-secretase to release amyloid peptides (Abeta40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Abeta40/42 is generated by gamma-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Abeta40 : 42 to favor Abeta42. One hypothesis to explain this outcome is that mutant PS alters the specificity of gamma-secretase to favor production of Abeta42 at the expense of Abeta40. To test this hypothesis in vivo, we studied Abeta40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Abeta42 and the rate of amyloid deposition. We further show that the shift in Abeta42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Abeta42, while maintaining a constant level of Abeta40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for gamma-secretase, but rather that they have more complex effects on the regulation of gamma-secretase and its access to substrates.