Lipocalin-type prostaglandin D synthase/β-trace is a major amyloid β-chaperone in human cerebrospinal fluid
Lipocalin-type prostaglandin D synthase/β-trace is a major amyloid β-chaperone in human cerebrospinal fluid
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DOI：
10.1073/pnas.0701585104
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发表时间：
2007-04-10
影响因子：
11.1
通讯作者：
Urade, Yoshihiro
中科院分区：
文献类型：
--
作者：
Kanekiyo, Takahisa;Ban, Tadato;Urade, Yoshihiro
淀粉样蛋白β (A β)肽从单体形态到聚集体的构象变化在阿尔茨海默病（AD）的发病机制中至关重要。在健康的大脑中，一些身份不明的伴侣似乎可以阻止A -的聚集。在这里，我们报道了脂钙素型前列腺素D合成酶(L-PGDS)/ β -trace，这是大脑中产生的最丰富的脑脊液（CSF）蛋白，在AD患者和AD模型Tg2576小鼠的淀粉样斑块中都存在。表面等离子体共振分析表明，L-PGDS/ β -痕量与A - β单体和原纤维紧密结合，具有高亲和力（K-D = 18-50 nM），并且L-PGDS/ β -痕量识别A - β中的残基25-28，这是其构象转变为β片结构的关键区域。硫黄素T荧光检测a β聚集的结果显示，L-PGDS/ β -痕量可抑制a β(1-40)和a β(1-42)在脑脊液生理范围（1-5 μ M）内的自发聚集。L-PGDS/beta-trace还能抑制50 μ M A β的种子依赖性聚集，K-i为0.75 μ M.而且，当免疫亲和层析法从CSIF中去除L-PGDS/beta-trace后，对人脑脊液中A β(1-40)聚集的抑制活性降低了60%。与野生型相比，在l - pgds缺失小鼠脑室内输注A β(1-42)后，A β的沉积量增加了3.5倍，而在l - pgds过表达小鼠中，A β的沉积量减少到23%。这些数据表明，L-PGDS/ β -trace是大脑中主要的内源性a- β伴侣，并提示该功能的紊乱可能参与了AD的发生和发展。我们的发现可能为阿尔茨海默病的诊断和治疗提供一种方法。
The conformational change in amyloid beta (A beta) peptide from its monomeric form to aggregates is crucial in the pathogenesis of Alzheimer's disease (AD). In the healthy brain, some unidentified chaperones appear to prevent the aggregation of A beta. Here we reported that lipocalin-type prostaglandin D synthase (L-PGDS)/beta-trace, the most abundant cerebrospinal fluid (CSF) protein produced in the brain, was localized in amyloid plaques in both AD patients and AD-model Tg2576 mice. Surface plasmon resonance analysis revealed that L-PGDS/beta-trace tightly bound to A beta monomers and fibrils with high affinity (K-D = 18-50 nM) and that L-PGDS/beta-trace recognized residues 25-28 in A beta, which is the key region for its conformational change to a beta-sheet structure. The results of a thioflavin T fluorescence assay to monitor A beta aggregation disclosed that L-PGDS/beta-trace inhibited the spontaneous aggregation of A beta (1-40) and A beta (1-42) within its physiological range (1-5 mu M) in CSF. L-PGDS/beta-trace also prevented the seed-dependent aggregation of 50 mu M A beta with K-i of 0.75 mu M. Moreover, the inhibitory activity toward A beta (1-40) aggregation in human CSF was decreased by 60% when L-PGDS/beta-trace was removed from the CSIF by immunoaffinity chromatography. The deposition of A beta after intraventricular infusion of A beta (1-42) was 3.5-fold higher in L-PGDS-deficient mice and reduced to 23% in L-PGDS-overexpressing mice as compared with their wild-type levels. These data indicate that L-PGDS/beta-trace is a major endogenous A beta-chaperone in the brain and suggest that the disturbance of this function may be involved in the onset and progression of AD. Our findings may provide a diagnostic and therapeutic approach for AD.