Herein, we show that TLQP-21 activation of C3aR1 increases microglial migration and phagocytosis, and that icv TLQP-21 administration to male 5-month-old 5xFAD mice reduces amyloid plaque burden and microgliosis, and restores expression of a subset of AD-associated genes to wild type levels. Here, C3AR1 is linked to Alzheimer disease.