Figure 4. Long-term CD22 blockade restores microglial homeostasis and improves cognitive function in aged mice.

a, Schematic of long-term CNS-targeted CD22 blockade.

b, c, Correlation of gene fold changes between microglia from anti-CD22 (n=7) and IgG (n=7) treated mice and between microglia from aged (22 m.o., n=3) and young (3 m.o., n=3) mice³⁶ (b) (R = −0.47, P=1.7e-12) or between microglia from 5xFAD (8.5 m.o., n=5) and age-matched WT (8.5 m.o., n=5) mice³⁷ (c) (R = −0.27, P=8.5e-6, blue line, linear regression, Spearman correlation). Genes differentially expressed (P<0.05, two-sided t-test) in either dataset (union) are shown.

d, Hierarchical clustering of gene fold changes between microglia from anti-CD22 (n=7) and IgG (n=7) treated mice, between microglia from aged (22 m.o., n=3) and young (3 m.o., n=3) mice³⁶, and between microglia from 5xFAD (8.5 m.o., n=5) and age-matched WT (8.5 m.o., n=5) mice³⁷. Genes differentially expressed (P-value<0.05, two-tailed t-test) in all three datasets (intersection) are shown.

e, f, g, h, Percentage of time spent in the novel arm of the forced alternation Y-maze (e, g) or displaying freezing behavior in a contextual fear conditioning test (f, h) for aged (18 m.o.) WT and CD22−/− mice (e, f, n=6) or aged (18 m.o.) WT mice treated with IgG or anti-CD22 (g, h, independent cohorts of mice in g (n=7 IgG, 9 anti-CD22) and h (n=7 for both groups)) (**P<0.005, *P<0.05, two-sided t-test; mean +/− s.e.m.).

i, Representative images of dentate gyri stained for Prox1 (white) and c-Fos (red) from IgG and anti-CD22 treated mice. White arrows indicate cFos+Prox1+ active granule neurons. Scale bar = 100 microns.

j, Total number of Prox1+c-Fos+ neurons in the dentate gyrus quantified over 5 tissue sections (n=7, *P<0.05, two-sided t-test; mean +/− s.e.m.).

Data in a, g, h, i, j were replicated in at least 2 independent experiments.