Koller Michael F, Mohajeri M Hasan, Huber Michael, Wollmer M Axel, Roth Z'graggen Birgit V, Sandmeier Erika, Moritz Eva, Tracy Jay, Nitsch Roger M, Christen Philipp
Institute of Biochemistry, Division of Psychiatry Research, University of Zürich, Zürich, Switzerland.
Neurodegener Dis. 2004;1(1):20-8. doi: 10.1159/000076666.
Heat-shock proteins are highly immunogenic. Complexed with an antigen, they act as adjuvants, inducing a humoral and cellular immune response against both the antigen and the chaperone. In this study, we produced an Hsp70-supported vaccine to induce the generation of antibodies against amyloid-beta (Abeta) peptides, the major constituent of beta-amyloid plaques in Alzheimer's disease. The vaccine consisted of synthetic human Abeta42 covalently cross-linked with DnaK, an Hsp70 homolog of Escherichia coli. Active immunization of mice with this vaccine resulted in the generation of antibodies against Abeta, that were detectable in sera after the first booster immunization. Antibody titers varied markedly with the genetic background of the mice. Prophylactic short-term immunization of transgenic mice (APP tg2576) before the onset of plaques, however, did not prevent amyloid plaque deposition. There were no differences in the plaque load and in the level of Triton X-100-soluble Abeta peptides in the brains of immunized and control-treated transgenic mice. Unexpectedly, the level of formic-acid soluble Abeta peptides tended to be higher in immunized mice. The reason for the increase may be an enhanced deposition of Abeta in the small cerebral blood vessels. These data emphasize the need for anti-Abeta antibodies that remove Abeta peptides from the central nervous system without negative side effects.
热休克蛋白具有高度免疫原性。与抗原结合后，它们作为佐剂，诱导针对抗原和伴侣蛋白的体液免疫和细胞免疫反应。在本研究中，我们制备了一种Hsp70支持的疫苗，以诱导产生针对淀粉样β（Aβ）肽的抗体，Aβ肽是阿尔茨海默病中β淀粉样斑块的主要成分。该疫苗由与人Aβ42合成肽共价交联的DnaK组成，DnaK是大肠杆菌的一种Hsp70同源物。用这种疫苗对小鼠进行主动免疫导致产生了针对Aβ的抗体，在首次加强免疫后血清中可检测到这些抗体。抗体滴度因小鼠的遗传背景而有显著差异。然而，在转基因小鼠（APP tg2576）斑块出现之前进行预防性短期免疫，并不能防止淀粉样斑块的沉积。免疫处理的转基因小鼠和对照处理的转基因小鼠大脑中的斑块负荷以及Triton X-100可溶性Aβ肽水平没有差异。出乎意料的是，免疫小鼠中甲酸可溶性Aβ肽水平往往更高。这种增加的原因可能是Aβ在脑小血管中的沉积增强。这些数据强调需要能够从中枢神经系统清除Aβ肽且无负面副作用的抗Aβ抗体。
