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

Abstract

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-Aβ antibodies 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.

M7G-related tumor immunity: novel insights of RNA modification and potential therapeutic targets

“…T cells constitute pivotal components of the adaptive immune system, encompassing distinct subtypes such as CD4 + and CD8 + αβ T cells, γδ T cells, and natural killer T (NKT) cells 80 . Upon recognition of cognate antigens by T cell receptors and subsequent stimulation by cytokines, naïve CD4 + and CD8 + T cells undergo a series of intricate biological processes.…”

Microglia in pediatric brain tumors: The missing link to successful immunotherapy

“…The choice of antibody isotype and design of the Fc effector can thereby significantly influence microglia behavior and the extent of neuroinflammation, making it an important consideration for any monoclonal antibody therapy applied in pediatric neuro-oncology. 99 …”

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

“…Upon activation via T cell receptor (TCR) signaling, T cells can differentiate further into a variety of subtypes, including CD45RO+ memory T cells (Tm), which are capable of maintaining a population within the body for decades. [16][17][18] In this study, we engineer CD4+ CD45RO+ memory helper T cells as IDUA enzyme producing factories in order to take advantage of the mobility and persistence of these cells. This approach using memory CD4+ T cells minimizes graft-versus-host disease (GVHD) in our animal model rather than using total CD3+ cells.…”