- 作者: Indre Dalgediene, Rita Lasickiene, Rima Budvytyte, Gintaras Valincius, Ramune Morkuniene, Vilmante Borutaite and Aurelija Zvirbliene
- 作者服務機構: Institute of Biotechnology, Vilnius University, V. Graiciuno str. 8, LT-02241 Vilnius, Lithuania
- 中文摘要: --
- 英文摘要:
Background: The central molecule in the pathogenesis of Alzheimer's disease (AD) is believed to be a small-sized polypeptide -- beta amyloid (Abeta) which has an ability to assemble spontaneously into oligomers. Various studies concerning therapeutic and prophylactic approaches for AD are based on the immunotherapy using antibodies against Abeta. It has been suggested that either active immunization with Abeta or passive immunization with anti-Abeta antibodies might help to prevent or reduce the symptoms of the disease. However, knowledge on the mechanisms of Abeta-induced immune response is rather limited. Previous research on Abeta1-42 oligomers in rat brain cultures showed that the neurotoxicity of these oligomers considerably depends on their size. In the current study, we evaluated the dependence of immunogenicity of Abeta1-42 oligomers on the size of oligomeric particles and identified the immunodominant epitopes of the oligomers.
Results: Mice were immunized with various Abeta1-42 oligomers. The analysis of serum antibodies revealed that small Abeta1-42 oligomers (1--2 nm in size) are highly immunogenic. They induced predominantly IgG2b and IgG2a responses. In contrast, larger Abeta1-42 oligomers and monomers induced weaker IgG response in immunized mice. The monoclonal antibody against 1--2 nm Abeta1-42 oligomers was generated and used for antigenic characterization of Abeta1-42 oligomers. Epitope mapping of both monoclonal and polyclonal antibodies demonstrated that the main immunodominant region of the 1--2 nm Abeta1-42 oligomers is located at the amino-terminus (N-terminus) of the peptide, between amino acids 1 and 19.
Conclusions: Small Abeta1-42 oligomers of size 1--2 nm induce the strongest immune response in mice. The N-terminus of Abeta1-42 oligomers represents an immunodominant region which indicates its surface localization and accessibility to the B cells. The results of the current study may be important for further development of Abeta-based vaccination and immunotherapy strategies. - 中文關鍵字: --
- 英文關鍵字: Alzheimer’s disease (AD), Amyloid beta (Aβ), Neurotoxicity, Immunogenicity, Neurotoxic oligomers, Epitope mapping