Intracellular tracing of amyloid vaccines through direct fluorescent labelling.
Intracellular tracing of amyloid vaccines through direct fluorescent labelling.
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DOI：
10.1038/s41598-018-20845-9
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发表时间：
2018-02-05
影响因子：
4.6
通讯作者：
Exley C
中科院分区：
文献类型：
--
作者：
Mold M;Kumar M;Mirza A;Shardlow E;Exley C
阿尔茨海默氏病是一种使人衰弱的神经退行性疾病，其逐渐引起突触丧失和主要神经元损伤。利用Aβ作为主动免疫原的免疫疗法或通过利用淀粉样蛋白抗体的被动治疗已显示出治疗前景。外周血单核细胞的迁移特性及其进入中枢神经系统的能力表明其在介导组织损伤和神经炎症中的有益作用。然而，这些细胞固有的吞噬特性使它们倾向于内化错误折叠的淀粉样蛋白生成肽，这些肽可以作为能够在大脑中形成淀粉样蛋白的种子。因此，控制淀粉样蛋白细胞命运的机制可能被证明是未来疫苗接种制度发展的关键。在此，我们已经开发出明确的和直接的构象敏感的荧光分子探针，揭示了胞浆内和核内的淀粉样蛋白的持久性在单核细胞辅助性T细胞1（THP-1）细胞系。在模拟疫苗制剂中使用致病性Aβ42物质作为模型抗原表明细胞内化的不同机制，其中纤维状淀粉样蛋白逃避溶酶体捕获，即使共沉积在颗粒状佐剂材料上。总的来说，抗原-佐剂复合物的直接荧光标记可以作为理解针对淀粉样变性和更广泛的痴呆症的疫苗中随后的免疫增强的关键工具。
Alzheimer’s disease is a debilitating neurodegenerative condition that progressively causes synaptic loss and major neuronal damage. Immunotherapy utilising Aβ as an active immunogen or via passive treatment utilising antibodies raised to amyloid have shown therapeutic promise. The migratory properties of peripheral blood-borne monocytes and their ability to enter the central nervous system, suggests a beneficial role in mediating tissue damage and neuroinflammation. However, the intrinsic phagocytic properties of such cells have pre-disposed them to internalise misfolded amyloidogenic peptides that could act as seeds capable of nucleating amyloid formation in the brain. Mechanisms governing the cellular fate of amyloid therefore, may prove to be key in the development of future vaccination regimes. Herein, we have developed unequivocal and direct conformation-sensitive fluorescent molecular probes that reveal the intracytoplasmic and intranuclear persistence of amyloid in a monocytic T helper 1 (THP-1) cell line. Use of the pathogenic Aβ42 species as a model antigen in simulated vaccine formulations suggested differing mechanisms of cellular internalisation, in which fibrillar amyloid evaded lysosomal capture, even when co-deposited on particulate adjuvant materials. Taken collectively, direct fluorescent labelling of antigen-adjuvant complexes may serve as critical tools in understanding subsequent immunopotentiation in vaccines directed against amyloidosis and wider dementia.
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影响因子：
4.6
作者：
Han S;Kollmer M;Markx D;Claus S;Walther P;Fändrich M
通讯作者：
Fändrich M
影响因子：
4.6
作者：
Mold M;Eriksson H;Siesjö P;Darabi A;Shardlow E;Exley C
通讯作者：
Exley C
DOI：
10.1073/pnas.0904532106
发表时间：
2010-02-02
影响因子：
11.1
作者：
Friedrich, Ralf P.;Tepper, Katharina;Faendrich, Marcus
通讯作者：
Faendrich, Marcus
影响因子：
16.6
作者：
Morimoto, Daichi;Walinda, Erik;Fukada, Harumi;Sou, Yu-Shin;Kageyama, Shun;Hoshino, Masaru;Fujii, Takashi;Tsuchiya, Hikaru;Saeki, Yasushi;Arita, Kyohei;Ariyoshi, Mariko;Tochio, Hidehito;Iwai, Kazuhiro;Namba, Keiichi;Komatsu, Masaaki;Tanaka, Keiji;Shirakawa, Masahiro
通讯作者：
Shirakawa, Masahiro
影响因子：
2.2
作者：
Mile, Irene;Svensson, Andreas;Eriksson, Hakan
通讯作者：
Eriksson, Hakan