Memapsin 2 (beta-secretase, BACE1) is the protease that initiates cleavage of beta-amyloid precursor protein leading to the production of amyloid-beta (Abeta) and the onset of Alzheimer's disease (AD). Reducing Abeta 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 Abeta 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 Abeta 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 Abeta40 and Abeta42 (approximately 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 Abeta production and improving cognitive function and that the current approach warrants further investigation as a therapy for AD.