Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor.
Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor.
复制标题
DOI：
10.3233/jad-160033
复制
发表时间：
2016-04-08
期刊：
影响因子：
--
通讯作者：
Buxbaum JN
中科院分区：
文献类型：
--
作者：
Li X;Song Y;Sanders CR;Buxbaum JN
在阿尔茨海默病（AD）中，大多数海马和皮质神经元显示抗甲状腺素运载蛋白（TTR）抗体染色增加。野生型TTR的遗传程序性过表达抑制了APP 23 AD模型小鼠的神经病理和行为异常，并且已经从一些人AD脑和APP 23转基因小鼠的脑中分离出TTR-Aβ复合物。在本研究中，体外NMR分析显示TTR的疏水性甲状腺素结合口袋与AβPP的β-分泌酶裂解释放的C99片段的胞质环之间存在相互作用，Kd = 86±9 µM。在表达两种蛋白质的培养细胞中，相互作用降低了C99的磷酸化（在T668处），并抑制了γ-分泌酶对其的切割，显著降低了Aβ分泌。结合其先前证实的抑制Aβ聚集（在组织培养中产生细胞毒性）的能力及其通过HSF 1的调节，这些发现表明TTR可以表现为AD发病机制的应激响应多模式抑制剂。
In Alzheimer’s disease (AD) most hippocampal and cortical neurons show increased staining with anti-transthyretin (TTR) antibodies. Genetically programmed over-expression of wild type human TTR suppressed the neuropathologic and behavioral abnormalities in APP23 AD model mice and TTR-Aβ complexes have been isolated from some human AD brains and those of APP23 transgenic mice. In the present study in vitro NMR analysis showed interaction between the hydrophobic thyroxine binding pocket of TTR and the cytoplasmic loop of the C99 fragment released by β-secretase cleavage of AβPP with Kd = 86±9 µM. In cultured cells expressing both proteins the interaction reduced phosphorylation of C99 (at T668) and suppressed its cleavage by γ-secretase significantly decreasing Aβ secretion. Coupled with its previously demonstrated capacity to inhibit Aβ aggregation (with the resultant cytotoxicity in tissue culture) and its regulation by HSF1 these findings indicate that TTR can behave as a stress responsive multimodal suppressor of AD pathogenesis.