Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
J Neurosci. 2011 Aug 31;31(35):12483-90. doi: 10.1523/JNEUROSCI.2417-11.2011.
Transthyretin (TTR), a systemic amyloid precursor in the human TTR amyloidoses, interacts with β-amyloid (Aβ) in vitro, inhibits Aβ fibril formation, and suppresses the Alzheimer's disease (AD) phenotype in APP23 mice bearing a human APP gene containing the Swedish autosomal dominant AD mutation. In the present study, we show that TTR is a neuronal product upregulated in AD. Immunohistochemical analysis reveals that, in contrast to brains from non-demented age-matched individuals and control mice, the majority of hippocampal neurons from human AD and all those from the APP23 mouse brains contain TTR. Quantitative PCR for TTR mRNA and Western blot analysis show that primary neurons from APP23 mice transcribe TTR mRNA, and the cells synthesize and secrete TTR protein. TTR mRNA abundance is greatly increased in cultured cortical and hippocampal embryonic neurons and cortical lysates from adult APP23 mice. Antibodies specific for TTR and Aβ pulled down TTR/Aβ complexes from cerebral cortical extracts of APP23 mice and some human AD patients but not from control brains. In complementary tissue culture experiments, recombinant human TTR suppressed the cytotoxicity of soluble Aβ aggregates added to mouse neurons and differentiated human SH-SY5Y neuroblastoma cells. The findings that production of Aβ, its precursor, or its related peptides induces neuronal TTR transcription and synthesis and the presence of Aβ/TTR complexes in vivo suggest that increased TTR production coupled with interaction between TTR and Aβ and/or its related peptides may play a role in natural resistance to human AD.
转甲状腺素蛋白（TTR）是人类 TTR 淀粉样变中的系统性淀粉样前体，它在体外与β-淀粉样蛋白（Aβ）相互作用，抑制 Aβ 纤维形成，并抑制携带包含瑞典常染色体显性 AD 突变的人 APP 基因的 APP23 小鼠的阿尔茨海默病（AD）表型。在本研究中，我们表明 TTR 是 AD 中上调的神经元产物。免疫组织化学分析显示，与非痴呆年龄匹配个体和对照小鼠的大脑相比，来自人类 AD 的大多数海马神经元和来自 APP23 小鼠大脑的所有神经元均含有 TTR。TTR mRNA 的定量 PCR 和 Western blot 分析表明，APP23 小鼠的原代神经元转录 TTR mRNA，并且细胞合成和分泌 TTR 蛋白。来自 APP23 小鼠培养的皮质和海马胚胎神经元以及来自成年 APP23 小鼠皮质裂解物的 TTR mRNA 丰度大大增加。针对 TTR 和 Aβ 的抗体从 APP23 小鼠和一些人类 AD 患者的大脑皮质提取物中拉下 TTR/Aβ 复合物，但不从对照大脑中拉下。在互补的组织培养实验中，重组人 TTR 抑制了添加到小鼠神经元和分化的人 SH-SY5Y 神经母细胞瘤细胞中的可溶性 Aβ 聚集体的细胞毒性。发现 Aβ、其前体或其相关肽的产生诱导神经元 TTR 转录和合成，以及体内存在 Aβ/TTR 复合物，表明增加的 TTR 产生与 TTR 和 Aβ 及其相关肽之间的相互作用可能在人类 AD 的天然抵抗中发挥作用。
