Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo University, Tokyo, Japan.
Tohoku J Exp Med. 2010 Feb;220(2):95-106. doi: 10.1620/tjem.220.95.
Based on the amyloid cascade hypothesis, various strategies targeting amyloid beta protein (Abeta) have been invented for prevention and treatment of Alzheimer disease (AD). Active and passive immunizations with Abeta and Abeta antibodies successfully reduced AD pathology and improved cognitive functions in an AD mouse model. However, active immunization with AN-1792, a mixture of Abeta1-42 peptide and adjuvant QS21 induced autoimmune encephalitis in humans. Surprisingly, although AN-1792 cleared senile plaque amyloid, it showed no benefit in humans. It is speculated that AN-1792 failed in deleting more toxic forms of Abeta such as oligomers and intracellular Abeta, suggesting that newly developing vaccines should delete these toxic molecules. Since T cell epitopes exist mainly in the C-terminal portion of Abeta, vaccines using shorter N-terminal peptides are under development. In addition, since T helper 1 (Th1) immune responses activate encephalitogenic T cells and induce continuous inflammation in the central nervous system, vaccines inducing Th2 immune responses seem to be more promising. These are N-terminal short Abeta peptides with Th2 adjuvant or Th2-stimulating molecules, DNA vaccines, recombinant viral vector vaccines, recombinant vegetables and others. Improvement of vaccines will be also achieved by the administration method, because Th2 immune responses are mainly induced by mucosal or trans-cutaneous immunizations. Here I review recent progress in active immunization strategies for AD.
基于淀粉样蛋白级联假说，已经发明了各种针对淀粉样蛋白 β（Abeta）的策略，用于预防和治疗阿尔茨海默病（AD）。用 Abeta 和 Abeta 抗体进行主动和被动免疫接种成功地减少了 AD 小鼠模型中的 AD 病理学并改善了认知功能。然而，用 Abeta1-42 肽和佐剂 QS21 的混合物 AN-1792 进行主动免疫接种会在人类中引起自身免疫性脑炎。令人惊讶的是，尽管 AN-1792 清除了老年斑淀粉样蛋白，但它对人类没有益处。据推测，AN-1792 未能清除更有毒的 Abeta 形式，例如寡聚物和细胞内 Abeta，这表明新开发的疫苗应该清除这些有毒分子。由于 T 细胞表位主要存在于 Abeta 的 C 末端部分，因此正在开发使用较短的 N 末端肽的疫苗。此外，由于 T 辅助 1（Th1）免疫反应激活致脑炎 T 细胞并在中枢神经系统中引起持续炎症，因此诱导 Th2 免疫反应的疫苗似乎更有前途。这些是具有 Th2 佐剂或 Th2 刺激分子的 N 末端短 Abeta 肽、DNA 疫苗、重组病毒载体疫苗、重组蔬菜等。通过给药方法也可以改善疫苗，因为 Th2 免疫反应主要由粘膜或经皮免疫诱导。在这里，我回顾了 AD 主动免疫策略的最新进展。
