Relative Ratio and Level of Amyloid-β 42 Surrogate in Cerebrospinal Fluid of Familial Alzheimer Disease Patients with Presenilin 1 Mutations
Relative Ratio and Level of Amyloid-β 42 Surrogate in Cerebrospinal Fluid of Familial Alzheimer Disease Patients with Presenilin 1 Mutations
复制标题
早老素1突变家族性阿尔茨海默病患者脑脊液中淀粉样蛋白-β42替代物的相对比例和水平
DOI：
10.1159/000355258
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Tagami et al.
中科院分区：
文献类型：
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作者：
Kondo D;Hino H;Shibuya K;Fujisawa K;Kosaka K;Hirayasu Y;Yamamoto R;Kasanuki K;Minegishi M;Sato K;Hosokawa M;Arai T;Arai H;Iseki E;Tagami et al.
背景与家族性阿尔茨海默病（FAD）相关的早老素1（Presenilin 1，PS1）突变通常会增加培养细胞分泌的淀粉样蛋白β 42（amyloid-β42，Aβ42）与Aβ40的比例。其中一些突变体减少Aβ40的分泌，而不是增加Aβ42的分泌。由于PS1-FAD患者脑内A β 42大量蓄积，难以估计Aβ42的分泌，因此，FAD患者脑内Aβ42/Aβ40比值升高是由Aβ42分泌升高还是Aβ 40分泌减少引起的尚不清楚。目的/方法收集PS1-FAD患者和神经功能正常患者（对照组）的脑脊液（CSF）。采用液相色谱-串联质谱法测定PS1-FAD患者脑脊液中淀粉样蛋白1-衍生Aβ样肽（APL 1 β）（包括APL 1 β28，Aβ42的替代标记物）的含量，并测定脑内Aβ42的分泌量。重要的是，CSF APL 1 β28没有显著升高。结论PS1-FAD患者脑脊液中A β42替代物的相对比例升高并非由于其在脑脊液中的含量增加，提示PS1-FAD患者脑内A β 42大量蓄积，而Aβ42分泌量无明显增加。
BackgroundPresenilin 1 (PS1) mutations associated with familial Alzheimer disease (FAD) generally increase the amyloid-β 42 (Aβ42) to Aβ40 ratio secreted in cultured cells. Some of these mutants reduce the secretion of Aβ40 rather than increase that of Aβ42. Since it has been difficult to estimate Aβ42 secretion in brains of PS1-FAD patients due to substantial Aβ42 accumulation, it remains unknown whether the enhanced Aβ42 to Aβ40 ratio in brains of FAD patients is caused by elevated Aβ42 secretion or by reduced secretion of Aβ40.Objective/MethodsCerebrospinal fluids (CSF) of PS1-FAD patients and neurological control patients (controls) were collected. Levels of CSF amyloid precursor-like protein-1-derived Aβ-like peptide (APL1β), including APL1β28, an Aβ42 surrogate marker, were quantified by liquid chromatography tandem mass spectrometry, and Aβ42 secretion in the brain was estimated.ResultsThe relative ratio of CSF APL1β28 to total APL1β was higher in PS1-FAD patients than in controls. Importantly, CSF APL1β28 was not significantly higher. However, C-terminally shorter CSF APL1β25 and APL1β27 were significantly lower in PS1-FAD patients and, as expected, so were CSF Aβ40 and Aβ42.ConclusionA higher relative ratio of the CSF Aβ42 surrogate in PS1-FAD patients is not due to its increase in CSF, suggesting that massive Aβ42 accumulation in the PS1-FAD brain occurs without an apparent increase in Aβ42 secretion.