Fig. 1: Lecanemab drives strong transcriptional changes in human microglia associated with Aβ plaques.
a–c, Representative high-magnification confocal z-stacks of CD45 (human microglia, blue), D54D2 (Aβ, green), IgG (human antibody, magenta) and a merged view with DAPI-stained nuclei (yellow). These high-resolution z-stacks are used to show the colocalization between D54D2 and IgG, as well as the internalization of Lecanemab within the microglia. Scale bar = 50 µm. Staining shown is representative; experiments were performed on four mice per condition for 8-week treatments and three mice per condition for 2-week treatments, all from the same treatment batch, and the experiments were repeated across two independent staining batches. a, After 8 weeks of Lecanemab administration, human IgG is detected in the brain parenchyma, where it associates with Aβ plaques and is internalized by human microglia (arrows). b, Notably, after 8 weeks of Lecanemab LALA-PG administration, IgG exhibits strong accumulation on D54D2 + Aβ plaques, indicating that a functional Fc fragment is necessary for uptake in microglia. c, This accumulation is already apparent as early as 2 weeks after the treatment in Lecanemab LALA-PG-treated mice. d, Representative large-field images of the Nova-ST data coupled with immunofluorescence workflow for Lecanemab-treated (top) and Lecanemab LALA-PG-treated (bottom) mice. Immunofluorescence was performed to visualize human microglia (CD45+, blue), Aβ plaques (D54D2+, green), Lecanemab or Lecanemab LALA-PG (magenta) and DAPI-stained nuclei (yellow). D54D2 signal was used to define the plaque regions (outlined in cyan). Left, a merged view; middle, D54D2; right, spatial transcriptomic TDs (spots binned into hexbins with a diameter of 40 µm) overlayed with plaque ROIs. TDs are colored based on their relative expression of human transcripts (purple, low expression; yellow, high expression). Scale bar = 100 µm. Images shown are representative; experiments were performed on one mouse per condition in each of two independent Nova-ST batches (total two mice per condition). e, Quadrant plot showing the log2(FC) of genes in Lecanemab-treated (x axis) and Lecanemab LALA-PG-treated (y axis) TDs with respect to their distance to plaques in the Nova-ST dataset. TDs were analyzed in the cortical regions of n = 2 mice per condition. A positive log2(FC) indicates upregulation in proximity to plaques. Red, genes significant in Lecanemab microglia only; purple, genes significant in Lecanemab LALA-PG microglia only; green, genes significant in both comparisons; gray, genes not significant in either comparison. log2(FC) were calculated using edgeR’s quasi-likelihood F test (two-sided); P values were adjusted using the BH correction (Padj < 0.05). f,g, From the differential gene expression analysis in e, we performed GSEA to further explore shifts in the microglia phenotype after the antibody treatment. We observed a significant positive enrichment of lysosome (f) and phagosome (g) genes in Lecanemab TDs near Aβ plaques (red), whereas such enrichment was not observed in Lecanemab LALA-PG TDs (purple). The vertical lines indicate the ES. Vertical tick marks along the x axis show the location of individual genes in the gene set within the log2(FC)-ranked gene list. The NES, two-sided Padj value and the leading-edge genes are shown for the GSEA performed on the Lecanemab and Lecanemab LALA-PG TDs. P values were adjusted using the BH correction. FC, fold change; ES, enrichment score; NES, normalized enrichment score. BH, Benjamini–Hochberg.
