The role of mutated amyloid beta 1⁃42 stimulating dendritic cells in a PDAPP transgenic mouse

Abstract

Background Amyloid plaque is one of the pathological hallmarks of Alzheimer's disease (AD). Anti⁃beta⁃amyloid (Aβ) immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. To avoid severe adverse effects such as meningoencephalitis induced by amyloid beta vaccine with adjuvant, and take advantage of amyloid beta antibody's therapeutic effect on Alzheimer's disease sufficiently, our group has developed a new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating dendritic cells (DC). Our previous work has confirmed that DC vaccine can induce adequate anti⁃amyloid beta antibody in PDAPP Tg mice safely and efficiently. The DC vaccine can improve impaired learning and memory in the Alzheimer's animal model, and did not cause microvasculitis, microhemorrhage or meningoencephalitis in the animal model. However, the exact mechanism of immunotherapy which reduces Aβ deposition remains unknown. In this report, we studied the mechanism of the vaccine, thinking that this may have implications for better understanding of the pathogenesis of Alzheimer's disease. Methods A new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating DC which were obtained from C57/B6 mouse bone marrow was developed. Amyloid beta with Freund's adjuvant was inoculated at the same time to act as positive control. After the treatment was done, the samples of brains were collected, fixed, cut. Immunohistochemical staining was performed to observe the expression of the nuclear hormone liver X receptor (LXR), membrane ⁃ bound protein tyrosine phosphatase (CD45), the ATP⁃binding cassette family of active transporters (ABCA1), receptor for advanced glycation end products (RAGE), β⁃site APP⁃cleaving enzyme (BACE) and Aβ in mouse brain tissue. Semi⁃ quantitative analysis was used to defect CA1, CA2, CA3, DG, Rad in hippocampus region and positive neuron in cortex region. Results Aβ was significantly reduced in the experimental group and the positive control group (P = 0.000), but no changes were seen in the negative control group. The levels of LXR, ABCA1, CD45, BACE expression were significantly higher in the PFDM group with DC vaccine treatment and the levels of RAGE were lower than those in the control group. Conclusion The reduction of Aβ via the DC vaccine occurs through multiple factors to achieve a new immune balance. The beneficial results of DC vaccine, which did not produce side effects, may be caused by the LXR/ABCA1 path. DC alone may play an important role in clearing the Aβ to prevent the occurrence of adverse reaction.

DOI：10.3969/j.issn.1672⁃6731.2012.03.016