The Effect Of IVIG On Alzheimer’s Disease And Its Correlation With Related Components And Functions Of IVIG

Objective:To investigate the efficacy of intravenous immunoglobulin(IVIG)from different manufacturers in China on Alzheimer’s disease(AD)and its correlation with its composition and function.Methods:1)To perform meta-analysis of clinical trials using IVIG to treat AD patients.Search for Chinese and English literature on IVIG for AD treatment published up to December 6,2021,through PubMed,Embase,Cochrane Library,ClinicalTrials.gov,China National Knowledge Infrastructure,and Wanfang.Metaanalysis was performed after screening the retrieved literature.2)To explore the efficacy of IVIG on AD from different manufacturers in China.Three-month-old 3xTg-AD and C57BL/6 mice were randomly divided into 5 groups:IVIG group(3xTg-AD+IVIG-A/B/C),experimental control group(3xTg-AD+saline)and blank control group(C57BL/6+saline).The injection dose was 1g/kg twice a week.After continuous administration for 12 weeks,the follow-up experiment was carried out after 12 weeks of normal feeding.The cognitive function of mice was detected by behavioral experiment,the pathology of hippocampus was analyzed by immunohistochemistry,and the differentially proteins in hippocampus were identified and verified by proteomics,Luminex and parallel response monitoring(PRM).3)To analyse the AD-related antibodies in IVIG.The content of anti-Aβ42,tau antibody and the ratio of p-tau antibody in IVIG were detected by ELISA.4)To evaluate the antiinflammatory effect of IVIG from different manufacturers in China.Seven-month-old Balb/c male mice were randomly divided into 5 groups:IVIG injection group(Balb/c+IVIG-A/B/C+LPS),control group(Balb/c+saline)and model group(Balb/c+LPS).The mice in the IVIG injection group were intraperitoneally injected with IVIG 1 g/kg,and control and the model group were given the same amount of normal saline once a day for 7 days.Finally,one hour after administration,IVIG injection group and model group were injected intraperitoneally with LPS(1 mg/kg),while control group was injected with the same amount of normal saline.The mice were killed the next day for blood analysis and histopathological examination.Results:1)A total of 5 randomized controlled clinical trials of IVIG in the treatment of AD were included after literature search and screening,involving 777 AD patients.Compared with placebo group,there was no significant difference in ADAS-cog score between IVIG group and placebo group,but there was significant improvement in ADCS-ADL and NPI score(P=0.01).No significant difference in all-cause discontinuation and adverse events were found.2)Compared with the control group,the total moving distance of the IVIG groups increased in the open field experiment(P<0.05).And only IVIG-C increased the target quadrant residence time of mice in the Barnes maze experiment and the object recognition index in the new object recognition experiment(P<0.05).Immunohistochemistry showed that Aβ deposition,tau protein phosphorylation and excessive activation of microglia and astrocytes in hippocampus were significantly inhibited in IVIG-C group(P<0.05).Luminex showed the level of inflammatory factors in brain was significantly decreased in IVIG-A and IVIG-C groups(P<0.05).Proteomics showed that the differential proteins and their interactions in IVIG-C group were mainly enriched in immune response and antigen processing and presentation.PRM further confirmed that the differential proteins in the IVIG-C group were mainly enriched in the MHC I molecular pathway.3)The concentration of anti-AP42 monomer antibody in IVIGA/B/C was 1.8 ± 0.1,3.5± 0.3,28.0 ± 0.3 μg/mL,the concentration of anti-Aβ42 oligomer antibody was 2.3 ± 0.1,7.9 ± 0.3,49.4 ± 1.9 μg/mL,the concentration of anti-tau antibody was 2.± 0.6,6.4± 0.9,33.3±3.6 μg/mL,and the ratio of anti-ptau antibody was 2.5,1.1,1.4 respectively.4)Compared with model group,the levels of serum IL-6 and TNF-α in IVIG-A and IVIG-B injection groups were significantly lower than those in inflammatory model group(P<0.05).In IVIG-C injection group.the white blood cell count,the levels of serum IL-6 and TNF-α were significantly reduced(P<0.05),the inflammatory injury of liver and kidney was significantly improved,the H-score was significantly decreased(P<0.05),and hyperactivation of microglia and astrocytes in the hippocampus were alleviated(P<0.05).Conclusion:The global clinical trials of IVIG in the treatment of AD are performed in Europe and the United States,and the overall efficacy is limited in patients with AD,but IVIG shows a good cognitive improvement effect in certain clinical trials.The therapeutic effects of IVIG from different manufacturers in China on 3xTg-AD mice are significantly different,and its efficacy may be positively correlated with the level of AD-related antibodies and anti-inflammatory ability in IVIG.IVIG-C has the potential to treat AD,which not only improves the cognitive and behavioral ability of 3xTg-AD mice,but also alleviates AD-related pathology and inhibits neuroinflammation,which may be related to the inhibition of antigen processing and presentation pathway of MHCI molecules in hippocampus.