Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Av, Ramón y Cajal s/n, Sant Joan d'Alacant E-03550, Spain.
Acta Neuropathol Commun. 2013 Aug 6;1:46. doi: 10.1186/2051-5960-1-46.
Presenilin-1 (PS1) is the active component of the amyloid precursor protein cleaving γ-secretase complex. PS1 protein is a transmembrane protein containing multiple hydrophobic regions which presence in cerebrospinal fluid (CSF) has not been measured to date. This study assesses whether PS1 and other components of the γ-secretase complex are present in CSF.
Here, we show that PS1 is present in ventricular post-mortem and lumbar ante-mortem CSF, and plasma as 100-150-kDa hetero-complexes containing both the N- and C-terminal fragments (NTF and CTF) of the protein. Immunoprecipitation and immunoblotting with different antibodies confirmed the identity of the PS1 species. The γ-secretase components, APH-1 (anterior pharynx-defective 1) and PEN-2 (presenilin enhancer 2), as well as presenilin-2 (PS2) fragments, co-exist within these CSF complexes, while nicastrin is not detected. These CSF-PS1 complexes differ from active γ-secretase membrane-complexes, and may represent nonspecific aggregation of the PS1 protein. Levels of PS1 complexes are increased in CSF samples from autopsy-confirmed Alzheimer's disease (AD) cases and were found to be more stable than complexes in CSF from control subjects. Despite similar levels of total PS1 in CSF from probable AD patients and cognitively normal subjects, an increased proportion of highly stable PS1 complexes were observed in AD CSF.
Our data suggest that fragments of the PS1 protein present in CSF as complexes may be useful as a biomarker for AD.
早老素 1（PS1）是淀粉样前体蛋白切割 γ-分泌酶复合物的活性成分。PS1 蛋白是一种跨膜蛋白，含有多个疏水区，但其在脑脊液（CSF）中的存在尚未得到测量。本研究评估 PS1 及 γ-分泌酶复合物的其他成分是否存在于 CSF 中。
在这里，我们表明 PS1 存在于脑室死后和腰前生前 CSF 以及血浆中，作为含有该蛋白的 N-和 C-末端片段（NTF 和 CTF）的 100-150kDa 异源复合物。用不同的抗体进行免疫沉淀和免疫印迹证实了 PS1 物质的身份。γ-分泌酶成分 APH-1（前咽缺陷 1）和 PEN-2（早老素增强子 2）以及 PS2 片段共同存在于这些 CSF 复合物中，而 nicastrin 未被检测到。这些 CSF-PS1 复合物与活性 γ-分泌酶膜复合物不同，可能代表 PS1 蛋白的非特异性聚集。在尸检确诊的阿尔茨海默病（AD）病例的 CSF 样本中，PS1 复合物的水平升高，并且比对照受试者 CSF 中的复合物更稳定。尽管 AD 患者和认知正常受试者 CSF 中的总 PS1 水平相似，但在 AD CSF 中观察到高度稳定的 PS1 复合物的比例增加。
我们的数据表明，作为复合物存在于 CSF 中的 PS1 蛋白片段可能作为 AD 的生物标志物有用。
