Neuroprotective Effects of IVIG against Alzheimer' s Disease via Regulation of Antigen Processing and Presentation by MHC Class I Molecules in 3xTg-AD Mice.

ABSTRACT

BACKGROUND: The results of clinical trials for Alzheimer's disease (AD) patients treated with Intravenous immunoglobulin (IVIG) revealed inconsistency in efficacy. OBJECTIVE: To explore the neuroprotective effects and possible mechanisms of different IVIG in 3xTg-AD mice. METHODS: 3-month-old 3xTg-AD mice were administered intraperitoneally with different IVIG (A/B/C) for 3 months and then the therapeutic effects were observed and tested at 9 months of age. The bioavailability of IVIG and Aß40/42 concentrations in parietotemporal cortex was measured by ELISA. Behavioral tests were performed to examine cognitive functions. Immunohistochemistry was utilized to examine the deposition of Aß, the phosphorylation of tau, the levels of GFAP and Iba-1 in the hippocampus. Proteomics, Luminex assay and parallel reaction monitoring were performed to identify and verify the proteins that showed a marked change in the hippocampus. RESULTS: IVIG-C was more effective than IVIG-A and IVIG-B in counteracting cognitive deficits, ameliorating Aß deposits and tau phosphorylation, attenuating the activation of microglia and astrocytes in the hippocampus and inhibiting the secretion of pro-inflammatory factors. IVIG-C affected innate immunity and suppressed the activation of antigen processing and presentation by MHC class I molecule (APP-MHC-I). CONCLUSION: The efficacy of different IVIG on AD was significantly different, and only IVIG-C has been confirmed to possess significant neuroprotective effects, which are related to the inhibition of APP-MHC-I. IVIG may be a potential therapeutic for AD but further research is needed to evaluate the functional of IVIG before clinical trials of AD treatment.