Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model

Passive immunotherapy is one of the most promising interventions for Alzheimer’s disease(AD).However,almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models.Here,we showed that Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ,antibody,and complement.Notably,anti-Aβantibodies without Fc fragment,or with blockage of CR3 or FcγRIIb,did not exert these adverse effects.Consistently,Aβ-targeting antibodies,but not their Fab fragments,significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment,whereas the memory impairments in mice were gradually rescued thereafter.Since the recovery rate of synapses in humans is much lower than that in mice,our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies.Therefore,Aβ-targeting antibodies lack of Fc fragment,or with reduced Fc effector function,may not induce microglial synaptic pruning,providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.

Efficient delivery of clay-based nanovaccines to the mouse spleen promotes potent anti-tumor immunity for both prevention and treatment of lymphoma

Cancer therapeutic nanovaccines are ideal tools to inhibit tumor growth and provide the body with continuous protecting immune surveillance.However,the conventional subcutaneous(SC)vaccination normally induces limited anti-tumor immune responses with low therapeutic efficacy.Herein,we devised clay-based nanovaccines and directly delivered them to the spleen via intravenous(IV)injection to induce the stronger anti-tumor immunity with higher efficacy for tumor prevention and treatment.The clay,i.e.,layered double hydroxide(LDH)was prepared as nanoadjuvant with the average size from 77 to 285 nm and co-loaded with the model antigen ovalbumin(OVA)and bioadjuvant CpG to form CpG/OVA-LDH(CO-LDH)nanovaccines.We found that CO-LDH-215(the size of LDH was 215 nm)promoted dendritic cells to present the most antigen,and moreover showed the highest spleen enrichment(~1.67%of CO-LDH-215 enriched in the spleen at 24 h post IV injection).The in vivo immunologic data showed that CO-LDH-215 induced the most potent anti-tumor immune responses and completely prevented the growth of E.G7-OVA tumor in the mouse model.Furthermore,IV injected CO-LDH-215 nanovaccine more effectively delayed tumor growth than that SC injected,largely due to the direct and quick delivery of more nanovaccines to the spleen.This study demonstrates that the therapeutic efficacy of nanovaccines can be greatly enhanced by targeted delivery of nanovaccines to the spleen via the proper vaccination route.