2024-09-03 バッファロー大学(UB)
The two main disease hallmarks of Alzheimer’s disease. which destroy neuronal networks, are amyloid plaques and neurofibrillary tangles.
<関連情報>
- https://www.buffalo.edu/news/releases/2024/09/Lovell-Alzheimers-vaccine.html
- https://www.sciencedirect.com/science/article/abs/pii/S0889159124005518
5価ペプチドワクチンがアルツハイマー病モデルマウスにおいて予防活性を有するAβ抗体とタウ抗体を誘発する A pentavalent peptide vaccine elicits Aβ and tau antibodies with prophylactic activity in an Alzheimer’s disease mouse model
Yiting Song, Chun-Ling Dai, Mitsuru Shinohara, Yunn Chyn Tung, Shiqi Zhou, Wei-Chiao Huang, Amal Seffouh, Yuan Luo, Matthew Willadsen, Yang Jiao, Maho Morishima, Yuko Saito, Seong-Ho Koh, Joaquin Ortega, Cheng-Xin Gong, Jonathan F. Lovell
Brain, Behavior, and Immunity Available online: 12 August 2024
DOI:https://doi.org/10.1016/j.bbi.2024.08.028
Highlights
- 5 peptides derived from Aβ and tau are displayed on immunogenic nanoliposomes.
- The epitopes are from Aβ (1–14 and pyroglutamate pE3-14) and tau (centered on phosphorylated pT181, pT217 and pS396/404).
- Immunization of mice with liposomes displaying 5 antigens induced antibodies against all epitopes without immune interference.
- Vaccine administration to 3xTg-AD mice using a prophylactical dosing schedule inhibited tau and amyloid pathologies resulting in improved cognitive function.
- Immunization was well tolerated and did not induce antigen-specific cellular responses or persistent inflammatory responses in the peripheral or central nervous system.
- Antibody levels could be reversed by halting monthly vaccinations.
Abstract
Amyloid-β (Aβ) and hyperphosphorylated tau protein are targets for Alzheimer’s Disease (AD) immunotherapies, which are generally focused on single epitopes within Aβ or tau. However, due to the complexity of both Aβ and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aβ peptides (1–14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404). These correspond to both soluble and aggregated targets and are displayed on the surface of immunogenic liposomes in an orientation that maintains reactivity with epitope-specific monoclonal antibodies. Intramuscular immunization of mice with individual epitopes resulted in minimally cross-reactive antibody induction, while simultaneous co-display of 5 antigens (“5-plex”) induced antibodies against all epitopes without immune interference. Post-immune sera recognized plaques and neurofibrillary tangles from human AD brain tissue. Vaccine administration to 3xTg-AD mice using a prophylactic dosing schedule inhibited tau and amyloid pathologies and resulted in improved cognitive function. Immunization was well tolerated and did not induce antigen-specific cellular responses or persistent inflammatory responses in the peripheral or central nervous system. Antibody levels could be reversed by halting monthly vaccinations. Altogether, these results indicate that active immune therapies based on nanoparticle formulations of multiple Aβ and tau epitopes warrant further study for treating early-stage AD.
