This study is the first to directly demonstrate in vivo that Lecanemab activates microglia via its Fc fragment to induce the molecular mechanism of Aβ plaque clearance, providing critical mechanistic insights into anti-Aβ immunotherapy for Alzheimer's disease.
Literature Overview
This paper, entitled 'The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia' and published in Nature Neuroscience, reviews and summarizes the mechanism of Lecanemab in Aβ pathology clearance. The study used a mouse model engrafted with human microglia combined with single-cell RNA sequencing and spatial transcriptomic analysis, revealing that Lecanemab activates microglia in a FcγR-dependent manner, thereby enhancing key functions such as phagocytosis, lysosomal degradation, metabolic reprogramming, and antigen presentation, which promote Aβ clearance. Additionally, the study identified SPP1/osteopontin as a key factor significantly upregulated during Lecanemab treatment and experimentally confirmed its role in Aβ clearance. These findings provide important clues for optimizing immunotherapy strategies for Alzheimer's disease.Background Knowledge
One of the major pathological features of Alzheimer’s disease (AD) is the deposition of β-amyloid (Aβ) into amyloid plaques. Accumulation of Aβ plaques is closely associated with neuroinflammation, neuronal damage, and cognitive decline; therefore, clearing these plaques has become a key therapeutic goal. In recent years, anti-Aβ monoclonal antibodies such as Lecanemab and Aducanumab have been developed to target and clear Aβ plaques. Although Lecanemab has shown some efficacy in clinical trials, its exact mechanism remains unclear. The traditional view holds that antibodies activate microglia via FcγR to promote Aβ phagocytosis and clearance, yet lacks direct in vivo evidence. Moreover, FcγR activation may trigger pro-inflammatory responses that could compromise therapeutic efficacy. Therefore, how to effectively clear Aβ plaques without inducing excessive inflammation has become a central challenge in current AD research. This study utilized a mouse model lacking endogenous microglia and engrafted with human microglia to evaluate the effects of Lecanemab and its Fc-silenced mutant (LALA-PG) on Aβ plaque clearance. The study also employed spatial transcriptomic and single-cell sequencing techniques to reveal the transcriptional programs induced by Lecanemab, providing mechanistic insights for future targeted regulation and therapeutic optimization.
Research Methods and Experiments
The research team used a human microglia-engrafted mouse model lacking endogenous microglia (AppNL-G-F Csf1rΔFIRE/ΔFIRE) to assess the effects of Lecanemab and its Fc-silent mutant (LALA-PG) on Aβ plaque clearance. Mice were administered 10 mg kg⁻¹ of Lecanemab or LALA-PG via intraperitoneal injection weekly for 8 weeks. Confocal microscopy was used to evaluate antibody localization in brain tissue and microglial phagocytosis of Aβ plaques. Additionally, the study employed spatial transcriptomics (Nova-ST) and single-cell RNA sequencing to analyze microglial transcriptional changes, particularly focusing on pathways related to phagosomes, lysosomes, antigen presentation, and metabolic reprogramming. Finally, through gene expression analysis, the researchers identified SPP1 (osteopontin) as significantly upregulated following Lecanemab treatment and validated its Aβ-clearing enhancing effects in both in vitro and in vivo experiments.Key Conclusions and Perspectives
Research Significance and Prospects
This study directly validated in an animal model the mechanism by which Lecanemab activates microglia through FcγR to clear Aβ, resolving a long-standing debate on whether antibody-mediated Aβ clearance is microglia-dependent. The discovery of SPP1 as a key effector factor in therapeutic response opens new avenues for developing adjuvant factors or biomarkers to enhance Aβ clearance. Moreover, this study supports the strategy of optimizing FcγR signaling in immunotherapy to improve efficacy and reduce side effects. Future studies may further explore the clinical potential of SPP1 and other Lecanemab-induced genes in AD therapy, as well as their roles in alternative anti-Aβ treatment modalities.
Conclusion
This study systematically elucidated the molecular mechanism by which Lecanemab clears Aβ plaques, confirming its dependence on microglial FcγR function. Using spatial transcriptomic and single-cell sequencing approaches, the study identified key gene programs involved in phagocytosis, degradation, and antigen presentation, and for the first time established SPP1 as a crucial factor in promoting Aβ clearance. These findings not only provide mechanistic support for anti-Aβ immunotherapy but also lay the foundation for optimizing future therapeutic strategies and developing personalized interventions. The study further highlights the central role of microglia in AD treatment, suggesting that functional reprogramming or targeted activation of microglial signaling pathways may be a key direction for next-generation immunotherapies.
