Effect Of Naturally Occurring Autoantibodies Against Aβ Oligomers From IVIG For Alzheimer’s Disease Treatment

Alzheimer’s diseaseacknowledged as progressive multifarious neurodegenerative disorder,is the leading cause of learning and memory loss in late adult life.Pathologically it is characterized by extracellular amyloidal protein deposits contributing to senile plaques,and intracellular neurofibrillary tangles(NFT)composed of an abnormally hyperphosphorylated and aggregated form of tau protein,and cerebral atrophy caused by neuronal loss,gliosis and inflammation.Increasing evidences show a variety of soluble oligomers derived from aggregated form of Aβ is a major pathogenic factor for the occurrence and development of AD.Previous reports showed that naturally occurring autoantibodies,intravenous immunoglobulin(IVIG),had the benefits in patients with moderate-stage AD who carried an APOE ε4 allele.However,the mechanism underlying IVIG played a role in patients remained unclear.In the present study,we investigated the properties of the antibodies against Aβ oligomers in IVIG in vitro and in vivo.Naturally occurring autoantibodies against Aβ oligomers(NAbs-Aβo),which were purified by Aβ42 oligomer or Cibacron blue affinity chromatography from IVIG and termed as Oli-NAbs and Blue-NAbs,respectively,specifically recognized the Aβ42 oligomers or both Aβ40 and 42 oligomers,inhibited Aβ42 aggregation and attenuated Aβ42-induced cytotoxicity in SH-SY5 Y neuroblastoma cells,but the flow though(Ft)which didn’t contain NAbs-Aβo couldn’t.Compared with vehicles,Oli-NAbs,Blue-NAbs and IVIG significantly improved the spatial memory and cognition,reduced soluble and oligomeric A? levels in APPswe/PS1dE9 transgenic mice.Further investigation showed that Blue-NAbs effectively decreased plaque burden and insoluble A? levels,while Oli-NAbs significantly depressed the microgliosis and astrogliosis,and the production of pro-inflammatory cytokines,including TNF-α and IL-6 in APPswe/PS1dE9 transgenic mice.It is concluded that as noted above,the oligomer-specific antibodies in IVIG at low levels were effective to improve the memory cognition and reduce soluble A? oligomer in AD mice,but to decrease the insoluble A? levels and plaque burden,or attenuate the neuroinflammation in AD mice,high levels of the antibodies against the oligomer of A?40 or A?42 were demanded,respectively.To reach the best effect,both kinds of antibodies were needed.IVIG are selected antibodies from thousands of healthy donors and contain thousands of antibodies against different antigens at very low levels.The isolation of NAbs-Aβo from IVIG didn’t interfere with the normal function of IVIG and the concentrated antibody by affinity chromatography exhibited more beneficial effects than IVIG,suggesting that NAbs-Aβo,as a safe agent,may be more feasible for the treatment of AD than IVIG.