CATHEPSIN B MODULATES MICROGLIAL MIGRATION AND PHAGOCYTOSIS OF AMYLOID β THROUGH PI3K-AKT SIGNALS IN ALZHEIMER’ S DISEASE

Abstract The approval of anti-Amyloid β (Aβ) monoclonal antibodies (lecanemab) in the treatment of patients with early Alzheimer’ s disease by FDA, suggests the reliability and importance of clearance of brain Aβ in AD therapy. Microglia are the main phagocytes in the brain to clean up Aβ, but the regulatory mechanism has not been fully clarified. Here, we investigated the critical role of cathepsin B (CatB) in modulating microglial clearance of Aβ in the mouse brain. We stereotaxically injected Aβ into the hippocampus of mice to assess the effect of CatB on Aβ clearance. CatB deficiency significantly reduced the Aβ clearance efficiency and aggravated the cognitive decline in mice after Aβ administration for 3 weeks. Exogenous Aβ increase CatB expression majorly in activated microglia. Transcriptomic analysis indicated that CatB is associated with gene clusters of migration, phagocytosis, and inflammation, which were validated by in vitro cell culture experiments. In addition, KEGG analysis and immunoblotting suggested that CatB modulates microglial Aβ clearance depending on PI3K-AKT activation. These findings indicate that CatB regulated microglial Aβ clearance activity, highlighting CatB as a therapeutic target for AD targeting Aβ clearance.