New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
J Alzheimers Dis. 2010;22(2):609-17. doi: 10.3233/JAD-2010-101029.
Gelsolin plays an important role in the fibrillogenesis of amyloid-β (Aβ). It binds to Aβ and inhibits its fibrillization. Gelsolin also gets proteolytically cleaved under apoptotic conditions. We recently reported a correlation between proteolytic product of gelsolin (carboxyl-terminal fragment of gelsolin, gelsolin-CTF) and severity of Alzheimer's disease. In this study, we report that gelsolin is cleaved in the brains of adult individuals (age, 43-63 years) with Down syndrome (DS), and that levels of gelsolin-CTF are significantly increased in the frontal cortex of adult DS subjects as compared to age-matched control subjects. Gelsolin-CTF was not observed in frontal cortex of young DS (age 0.5-23 years) and age-matched control subjects. In addition, the levels of both soluble and total Aβ40 and Aβ42 were significantly increased in the frontal cortex of adult DS patients as compared to age-matched control subjects. A positive relationship was observed between gelsolin-CTF in frontal cortex of DS, and the levels of soluble Aβ40 (r2= 0.7820, p < 0.01) and Aβ42 (r2 = 0.8179, p < 0.01). Experiments with recombinant full-length gelsolin and its N-terminal and C-terminal fragments showed that similar to gelsolin, proteolytic fragments of gelsolin can also interact with soluble synthetic Aβ. The post-translational modification of gelsolin proteins may not be essential as these proteins (overexpressed in Escherichia coli) were able to form complexes with Aβ. These results suggest that there may be a relationship between proteolytic cleavage of gelsolin and increased Aβ in the brain. Since soluble non-fibrillar forms of Aβ are neurotoxic, they may be involved in apoptosis and proteolysis of gelsolin.
凝溶胶蛋白在淀粉样β（Aβ）的纤维形成中起着重要作用。它与 Aβ结合并抑制其纤维形成。在凋亡条件下，凝溶胶蛋白也会被蛋白水解切割。我们最近报道了凝溶胶蛋白的蛋白水解产物（凝溶胶蛋白羧基末端片段，gelsolin-CTF）与阿尔茨海默病严重程度之间的相关性。在这项研究中，我们报告在患有唐氏综合征（DS）的成年个体（年龄 43-63 岁）的大脑中发现凝溶胶蛋白被切割，并且与年龄匹配的对照组相比，成年 DS 受试者的额皮质中的 gelsolin-CTF 水平显著增加。在年轻的 DS（年龄 0.5-23 岁）和年龄匹配的对照组的额皮质中未观察到 gelsolin-CTF。此外，与年龄匹配的对照组相比，在成年 DS 患者的额皮质中可溶性和总 Aβ40 和 Aβ42 的水平均显著增加。DS 患者额皮质中的 gelsolin-CTF 与可溶性 Aβ40（r2=0.7820，p<0.01）和 Aβ42（r2=0.8179，p<0.01）的水平呈正相关。用重组全长凝溶胶蛋白及其 N 端和 C 端片段进行的实验表明，与凝溶胶蛋白相似，凝溶胶蛋白的蛋白水解片段也可以与可溶性合成 Aβ相互作用。凝溶胶蛋白的翻译后修饰可能不是必需的，因为这些蛋白（在大肠杆菌中过表达）能够与 Aβ形成复合物。这些结果表明，凝溶胶蛋白的蛋白水解切割与大脑中 Aβ的增加之间可能存在关系。由于可溶性非纤维形式的 Aβ具有神经毒性，它们可能参与了凋亡和凝溶胶蛋白的蛋白水解。
