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How does aducanumab trigger microglial clearance of amyloid plaques?
Executive Summary
Aducanumab promotes microglial clearance of amyloid-beta (Aβ) plaques primarily by binding aggregated Aβ and engaging microglial Fc receptors, which increases phagocytosis and alters plaque structure to favor removal; multiple recent studies report dose-dependent plaque lowering and microglial activation signatures after immunization [1] [2] [3]. Evidence from human tissue and advanced in vitro and animal models shows that aducanumab and similar anti-Aβ antibodies both recruit immune mechanisms—phagocytosis, complement engagement, and changes in microglial transcriptional states—yet the treatments also shift microglial phenotypes and carry safety tradeoffs such as amyloid-related imaging abnormalities, and the precise molecular cascade remains incompletely resolved [4] [5] [6].
1. How binding converts plaques into targets: antibody engagement and structural effects that matter
Aducanumab’s Fab domain selectively binds aggregated Aβ in oligomeric and fibrillar states rather than monomers, which decorates plaques and generates antibody-amyloid complexes that are more recognizable to microglia; this selective targeting is central to observed reductions in soluble and insoluble Aβ across models and human samples [6] [1]. Several analyses report that aducanumab can prevent formation of larger aggregates and dissolve fibrillar structures in neurosphere and animal experiments, a physical remodeling that likely presents more accessible epitopes and reduces dense-core resistance to uptake [3] [2]. That remodeling correlates with dose-dependent lowering of plaque burden and with downstream biomarker changes, implying that structural alteration of plaques is a proximal mechanism enabling microglial clearance [7] [8].
2. Microglial recruitment and Fc-driven phagocytosis: the immune handoff
Once plaques are antibody-coated, the exposed Fc portion of aducanumab engages microglial Fc receptors, initiating activation programs that increase phagocytic uptake of Aβ; this Fc–FcR interaction is the canonical pathway to stimulate microglial engulfment and is invoked repeatedly across mechanistic summaries [2] [1]. Live imaging and 3D culture studies demonstrate accelerated phagocytosis and reduced intracellular aggregated Aβ in microglia treated with aducanumab, indicating enhanced clearance kinetics rather than solely passive displacement of Aβ [3]. Human immunization and passive antibody studies document transcriptional shifts in microglia toward activation states enriched for phagocytosis and complement signaling, suggesting that Fc engagement triggers a coordinated cellular program beyond immediate uptake [4].
3. Transcriptional reprogramming: activation signatures, antigen presentation, and mixed phenotypes
Multiple recent datasets show that anti-Aβ immunotherapies attenuate classical disease-associated microglial (DAM) signatures in proportion to plaque reduction while leaving residual plaque-associated microglia with a hybrid phenotype that includes antigen-presentation and complement-expression genes [7] [4]. Some studies report a dose-dependent reduction in DAM activation and glycolytic markers in bulk RNA-seq, whereas single-cell and tissue analyses reveal microglial subtypes that become enriched for complement and phagocytosis pathways after immunization, pointing to a shift in functional state rather than simple binary activation [7] [4]. These transcriptional changes may explain both improved clearance at some plaques and persistent microglial involvement at residual deposits, emphasizing complexity in response and potential implications for downstream inflammation [5].
4. Tradeoffs and limitations: inflammation, ARIA, and translational caveats
Immunotherapy that recruits microglia also risks pro-inflammatory skewing and amyloid-related imaging abnormalities (ARIA); clinical and preclinical reports link plaque removal with imaging changes, and models show that chronic microglial activation can exacerbate neuroinflammation and neurite dystrophy if unchecked [1] [5]. Several studies caution that anti-Aβ treatment preferentially reduces loosely aggregated fibrils and is most effective when plaques are less dense, implying that timing matters and that late-stage, heavily aggregated pathology may be less amenable to microglial-mediated clearance [7]. Limitations in existing literature include reliance on mouse models without tau pathology or neurodegeneration and divergent treatment windows between preclinical early intervention paradigms and human trials that often enroll already amyloid PET–positive patients [7] [5].
5. Where the evidence converges—and where questions remain
Convergent evidence across human tissue, in vitro 2D/3D systems, and animal models supports a model where aducanumab tags aggregated Aβ, remodels plaque structure, engages Fc receptors and complement, and reprograms microglia to phagocytose antibody-coated material, yielding dose-dependent plaque reductions and transcriptional signatures associated with clearance [3] [4] [2] [1]. Unresolved issues persist about the exact intracellular signaling cascades, the long-term consequences of induced microglial states, variability in clearance of dense-core versus diffuse plaques, and how these mechanisms translate to meaningful clinical benefit given safety signals and variable cognitive outcomes reported across trials [7] [6]. Further mechanistic work linking molecular events to functional outcomes in human-relevant systems is required to close these gaps.