β-Amyloid (Aβ) plaque in the brains of patients with Alzheimer's disease (AD) is mainly caused by impaired clearance of Aβ by glial cells, including microglia and astrocytes. Because microglia play an important protective role in the central nervous system, many efforts have been made to identify agents that effectively improve microglial Aβ phagocytosis. This study found that TLQP-21, which is cleaved from VGF (VGF nerve growth factor inducible) precursor protein, enhanced Aβ phagocytosis and degradation by microglial BV2 cells. TLQP-21 also improved microglial phagocytic activity and promoted fibrillar amyloid-β (fAβ) uptake by microglial BV2 cells via a C3AR1-dependent mechanism. Moreover, TLQP-21 stimulated Aβ degradation by enhancing lysosome activity, thereby enhancing fAβ clearance. These results suggest that treatment with TLQP-21 may be a novel therapeutic strategy to efficiently enhance microglial Aβ clearance in AD.,Copyright © 2020 Elsevier Inc. All rights reserved.