Sogorb-Esteve Aitana, García-Ayllón María-Salud, Fortea Juan, Sánchez-Valle Raquel, Lleó Alberto, Molinuevo José-Luis, Sáez-Valero Javier
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, 03550, Av. Ramón y Cajal s/n, Sant Joan d'Alacant, E-03550, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Sant Joan d'Alacant & Barcelona, Spain.
Mol Neurodegener. 2016 Sep 29;11(1):66. doi: 10.1186/s13024-016-0131-2.
Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzheimer's disease (AD), particularly in both symptomatic and asymptomatic genetically determined AD, in order to evaluate their potential as early biomarkers.
Western blotting, differential centrifugation and co-immunoprecipitation served to determine and characterize CSF-PS1 complexes. We also monitored the assembly of soluble PS1 into complexes in a cell model, and the participation of Aβ in the dynamics and robustness of the stable PS1 complexes.
There was an age-dependent increase in CSF-PS1 levels in cognitively normal controls, the different complexes represented in similar proportions. The total levels of CSF-PS1, and in particular the proportion of the stable 100-150 kDa complexes, increased in subjects with autosomal dominant AD that carried PSEN1 mutations (eight symptomatic and six asymptomatic ADAD) and in Down syndrome individuals (ten demented and ten non-demented DS), compared with age-matched controls (n = 23), even prior to the appearance of symptoms of dementia. The proportion of stable CSF-PS1 complexes also increased in sporadic AD (n = 13) and mild-cognitive impaired subjects (n = 12), relative to age-matched controls (n = 17). Co-immunoprecipitation demonstrated the association of Aβ oligomers with soluble PS1 complexes, particularly the stable complexes.
Our data suggest that CSF-PS1 complexes may be useful as an early biomarker for AD, reflecting the pathology at asymptomatic state.
早老素-1（PS1）是膜内γ-分泌酶复合物的活性成分，可在脑脊液（CSF）中检测为可溶性异聚体聚集体。本研究的目的是检查阿尔茨海默病（AD）患者腰椎脑脊液（CSF-PS1）中不同的可溶性PS1复合物，特别是有症状和无症状的基因决定的AD患者，以评估它们作为早期生物标志物的潜力。
蛋白质印迹法、差速离心法和免疫共沉淀法用于确定和表征CSF-PS1复合物。我们还监测了可溶性PS1在细胞模型中组装成复合物的过程，以及Aβ在稳定PS1复合物的动力学和稳定性中的作用。
认知正常对照组的CSF-PS1水平随年龄增长而增加，不同复合物的比例相似。与年龄匹配的对照组（n = 23）相比，携带PSEN1突变的常染色体显性AD患者（8例有症状和6例无症状ADAD）和唐氏综合征患者（10例痴呆和10例非痴呆DS）的CSF-PS1总水平，特别是稳定的100-150 kDa复合物的比例增加，甚至在痴呆症状出现之前。相对于年龄匹配的对照组（n = 17），散发性AD（n = 13）和轻度认知障碍患者（n = 12）中稳定CSF-PS1复合物的比例也增加。免疫共沉淀证明Aβ寡聚体与可溶性PS1复合物相关，特别是稳定复合物。
我们的数据表明，CSF-PS1复合物可能作为AD的早期生物标志物有用，反映无症状状态下的病理情况。
