Schwarzman A L, Goldgaber D
Department of Psychiatry, School of Medicine, State University of New York at Stony Brook 11794-8101, USA.
Ciba Found Symp. 1996;199:146-60; discussion 160-4. doi: 10.1002/9780470514924.ch10.
Aggregated amyloid beta-protein (A beta) is a key component of the amyloid depositions found in the brains of patients with Alzheimer's disease. In contrast, in cerebrospinal fluid (CSF), A beta is found in a soluble form. The analysis of complexes of A beta with CSF proteins in a KBr gradient revealed an association of A beta only with free proteins and not with lipoprotein particles. Transthyretin (TTR), a second major CSF protein, formed SDS-stable complexes with A beta and significantly decreased the rate of A beta fibril formation. In physiological buffers and CSF, TTR exclusively decreased the level of A beta pentamers. Endogenous TTR-A beta complexes were detected in human CSF by immunoprecipitation. Using site-directed mutagenesis and computer-assisted modelling, we identified amino acid residues on the surface of the TTR monomer that interact with A beta. Specific TTR immunoreactivity was detected in multiple cortical neurons and astrocytes in the human brain. We propose that A beta binding proteins play a key role in the modulation of A beta aggregation and normally prevent amyloid formation in biological fluids and in the brain.
聚集的β-淀粉样蛋白（Aβ）是在阿尔茨海默病患者大脑中发现的淀粉样沉积物的关键成分。相比之下，在脑脊液（CSF）中，Aβ以可溶形式存在。在KBr梯度中对Aβ与脑脊液蛋白复合物的分析表明，Aβ仅与游离蛋白相关，而与脂蛋白颗粒无关。转甲状腺素蛋白（TTR）是脑脊液中的第二种主要蛋白，它与Aβ形成SDS稳定复合物，并显著降低Aβ纤维形成的速率。在生理缓冲液和脑脊液中，TTR专门降低Aβ五聚体的水平。通过免疫沉淀在人脑脊液中检测到内源性TTR-Aβ复合物。利用定点突变和计算机辅助建模，我们确定了TTR单体表面与Aβ相互作用的氨基酸残基。在人脑中多个皮质神经元和星形胶质细胞中检测到特异性TTR免疫反应性。我们认为，Aβ结合蛋白在调节Aβ聚集过程中起关键作用，通常可防止生物体液和大脑中淀粉样蛋白的形成。
