Memapsin 2 (-secretase, BACE1) is the protease that initiates cleavage of -amyloid precursor protein leading to the production of amyloid- (A) and the onset of Alzheimer’s disease (AD). Reducing A by targeting memapsin 2 is a major strategy in developing new AD therapy. Here, in a proof-of-concept study, we show that immunization of transgenic AD mice (Tg2576) with memapsin 2 resulted in A reduction and cognitive improvement. To study the basis of this therapy, we demonstrated that anti-memapsin 2 (anti-M2) antibodies were rapidly internalized and reduced A production in cultured cells. These antibodies also effectively crossed the blood-brain barrier to reach the brain. Two- and 10-month Tg2576 mice were immunized and monitored over 10 and 6 months, respectively. We observed a significant decrease of plasma and brain A₄₀ and A₄₂ (35%) in the immunized mice as compared to controls. Immunized mice also showed better cognitive performance than controls in both cohorts. Brain histological analyses found no evidence of T cell/microglia/astrocyte activation in the immunized mice, suggesting the absence of inflammatory responses. These results suggest that memapsin 2 immunization in Tg2576 was effective in reducing A production and improving cognitive function and that the current approach warrants further investigation as a therapy for AD.--Chang, W.-P., Downs, D., Huang, X.-P., Da, H., Fung, K. M., Tang, J. Amyloid-beta reduction by memepsin 2 (beta-secretase) immunization.