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Amyloid-beta reduction by memapsin 2 (beta-secretase) immunization

Wan-Pin Chang^*,1, Deborah Downs^*, Xiang-Ping Huang^*, Huining Da^*, Kar-Ming Fung and Jordan Tang^*,,1

^* Protein Studies Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA;

Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; and

Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA

¹Correspondence: Protein Studies Program, Oklahoma Medical Research Foundation, 825 N.E. 13th St., Oklahoma City, OK 73104, USA. E-mail: jordan-tang{at}omrf.ouhsc.edu; wanpin-chang{at}omrf.ouhsc.edu

Memapsin 2 (ß-secretase, BACE1) is the protease that initiates cleavage of ß-amyloid precursor protein leading to the production of amyloid-ß (Aß) and the onset of Alzheimer’s disease (AD). Reducing Aß 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 Aß 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 Aß 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 Aß₄₀ and Aß₄₂ (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 Aß 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.

Key Words: immunotherapy • Alzheimer’s disease • BACE1