Cathepsin B modulates microglial migration and phagocytosis of amyloid β in Alzheimer’s disease through PI3K-Akt signaling

The approval of anti-amyloid β (Aβ) monoclonal antibodies (lecanemab) for the treatment of patients with early preclinical stage of Alzheimer’s disease (AD) by the Food and Drug Administration, suggests the reliability and importance of brain Aβ clearance for AD therapy. Microglia are the main phagocytes that clear Aβ in the brain, but the underlying regulatory mechanism is unclear. Here, we investigate the critical role of cathepsin B (CatB) in modulating microglial Aβ clearance from mouse brain. Wild-type or CatB^−/− mice were injected with Aβ into the hippocampus from 1 to 3 weeks. Mice were evaluated for cognitive change, Aβ metabolism, neuroinflammation. Microglia and neuron cultures were prepared to verify the in vivo results. The statistical analyses were performed by student’s t test, one-way ANOVA with a post hoc Tukey’s test using the GraphPad Prism software package. CatB deficiency significantly reduces Aβ clearance efficiency and aggravates mouse cognitive decline. Exogenous Aβ markedly increases CatB expression in activated microglia. Transcriptome analysis and in vitro cell culture experiments demonstrate that CatB is associated with gene clusters involved in migration, phagocytosis, and inflammation. In addition, transcriptome analysis and immunoblotting suggest that CatB modulates microglial Aβ clearance via PI3K-AKT activation. Our study unveils a previously unknown role of CatB in promoting microglial functionality during Aβ clearance.