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A Novel Mechanism of Immunotherapy for Alzheimer’s Disease: Microglia-Mediated Targeted Clearance of Amyloid Plaques

　　Introduction

　　The plaque‑clearing efficacy of amyloid‑targeting immunotherapies is highly dependent on microglial activation, yet this mechanism had previously lacked robust empirical support. At the recent Alzheimer’s & Parkinson’s Disease (AD/PD) International Conference held in Copenhagen, Denmark, several studies have helped to fill this critical gap in our understanding of the underlying mechanisms.

　　The research team led by Giulia Albertini at KU Leuven reported that, in mouse models, lecanemab loses its ability to bind to microglia, or when microglia are depleted, the antibody fails to mediate plaque clearance. Furthermore, in vitro experiments using brain tissue sections from Alzheimer’s disease patients conducted by Lars Lannfelt’s group at Uppsala University demonstrated that lecanemab can induce macrophage phagocytosis of amyloid‑β; however, blocking Fcγ receptors on the cell surface to disrupt antibody–cell interactions completely abolished this phagocytic activity. Lis de Weerd of Ludwig Maximilian University of Munich argues that these findings provide robust evidence that microglia serve as the central effector cells in amyloid‑β immunotherapy.

　　01 Microglial Activation and Transcriptional Reprogramming of DAM Genes

　　The study confirms that targeted activation of microglia is a prerequisite for lecanemab-mediated plaque clearance. Activated microglia initiate the transcription of disease-associated microglia (DAM)-specific genes, such as osteopontin.

　　To obtain functional data, Albertini and Bart De Strooper conducted an in-depth analysis using chimeric mouse models. The research team introduced a three‑amino‑acid mutation into the Fc domain of lecanemab, generating a mutant variant (lecanemab LALA‑PG) that cannot bind to human microglial Fcγ receptors. In four‑month‑old APPNL‑G‑F mice expressing human microglia, antibody injections were administered for eight weeks. The results showed that both antibody variants effectively targeted and coated amyloid plaques. Although the number of microglia recruited around the plaques was comparable across groups, only the fully functional lecanemab promoted cellular uptake of amyloid, achieving simultaneous clearance of antibodies and plaques and reducing total plaque burden by 50%. By contrast, after treatment with the inactive lecanemab, although plaques were coated by antibodies and surrounded by microglia, they remained uncleared, and the LALA‑PG mutant exhibited no plaque‑clearing activity. Further experiments demonstrating microglial clearance confirmed that, in APPNL‑G‑F mice lacking these cells, lecanemab’s plaque‑clearing function was entirely abolished.

　　

 

　　Figure 1: Microglia-mediated plaque clearance depends on the Fc‑domain function of antibodies. After 8 weeks of treatment with non‑functional lencainumab (bottom), amyloid plaques (green) in the brains of chimeric mice remained uncleared, appearing as deposits surrounded by antibodies (pink) and microglia (blue). In contrast, functional lencainumab (top) successfully activated microglia and achieved simultaneous clearance of both plaques and antibody‑bound aggregates. (Image source: Giulia Albertini)

　　Spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) analyses reveal that lecanemab primarily activates microglia by stimulating antigen presentation, phagocytosis, and lysosomal degradation pathways, while broadly upregulating the expression of DAM genes. The most pronounced transcriptional changes were observed in the gene encoding secreted phosphoprotein 1 (SPP1), with lecanemab treatment nearly doubling its expression level. As a pro-inflammatory glycoprotein, SPP1 promotes phagocytosis, remodels the extracellular matrix, and triggers a cascade of additional DAM gene upregulation. These findings suggest that lecanemab may reinitiate the stalled clearance of pathological proteins in the AD brain by further enhancing the already low-level expression of SPP1.

　 　02 Direct Effects and Target Specificity of Osteopontin

　　Studies using brain tissue sections from amyloid‑prone mouse models have confirmed the direct effects of osteopontin: upon its introduction, microglia are activated and efficiently clear amyloid plaques; conversely, in the absence of this protein, plaque clearance is impaired.

　　In vitro experiments demonstrated that co-culturing osteopontin with human microglia in APPNL‑G‑F mouse brain tissue induces gene expression profiles similar to those observed following treatment with lecanemab, and the efficiency of plaque clearance exhibits a dose‑dependent positive correlation with osteopontin levels.

　　Notably, although previous studies have shown that osteopontin can induce deleterious aberrant synaptic pruning in specific mouse models, lenacapavir treatment did not reduce the number of synapses surrounding amyloid plaques. This suggests that the antibody possesses a safety profile that tightly restricts phagocytic targeting to amyloid deposits.

　　

 

　　Figure 2: Osteopontin directly drives the phagocytic activity of microglia. In brain slices from amyloid‑prone mice, addition of osteopontin (right) markedly activates microglia (pink) to phagocytose and clear amyloid plaques (blue). By contrast, in the control group lacking this protein (left), microglial clearance is impaired. (Image source: Giulia Albertini)

　　03 Antibody Binding Kinetics and Microenvironment Remodeling

　　In vitro cytological experiments likewise support the necessity of targeting the receptor. In cultured monocytes, lecanemab promotes the internalization of Aβ protofibrils; however, when lecanemab fails to bind FcγRs on the monocyte surface, the extent of Aβ uptake does not differ significantly from that observed in the absence of antibody or in the presence of a control antibody.

　　

 

　　Figure 3: Blocking Fcγ receptors markedly inhibits monocyte uptake of Aβ. In the presence of lecanemab (upper right), monocytes (nuclei shown in blue) extensively internalize Aβ protofibrils (green). When antibody binding to Fcγ receptors is blocked (lower right), the level of Aβ internalization drops to baseline levels comparable to those observed in the antibody‑free group (upper left) or the control group (lower left). (Image source: Lars Lannfelt)

　　Lannfelt applied lecanemab and differentiated macrophages to fresh AD brain tissue sections and observed a dose‑dependent clearance of amyloid plaques, an effect that was almost completely reversed by specific blockade of FcγRs. Lannfelt proposed that, given lecanemab’s preferential targeting of Aβ protofibrils rather than mature plaques, its mechanism may involve disrupting the dynamic equilibrium among different Aβ species, thereby promoting the dissociation and dispersal of aggregates within the plaques, which are then captured and cleared by the antibody.

　　Furthermore, the topological binding characteristics of antibodies also influence clinical efficacy. Structural analyses indicate that, compared with aducanumab, lecanemab can more densely coat Aβ42 protofibrils. Kenjiro Ono of Kanazawa University used atomic force microscopy at sub-nanometer resolution to reveal the physical underpinnings of antibody‑binding kinetics: lecanemab forms an exceptionally thick and highly dense surface coating that physically prevents further aggregation and elongation of protofibrils into globular oligomers.

　　The data presented by Ono indicate that aducanumab’s coating layer is relatively thin, failing to effectively prevent the extension of aggregation‑level fibrils. This provides a mechanistic explanation—at the structural‑physical level—for its comparatively modest clinical efficacy. Taken together, all current evidence suggests that the physiological potency of antibody‑mediated microglial activation via FcγR signaling, along with the high‑density binding characteristics of its spatial conformation, constitute the two most critical determinants of whether amyloid‑targeting immunotherapies can successfully clear plaques.

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