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Amyloid‐beta reduction by memapsin 2 (beta‐secretase) immunization
Author(s) -
Chang WanPin,
Downs Deborah,
Huang XiangPing,
Da Huining,
Fung KarMing,
Tang Jordan
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7993com
Subject(s) - microglia , immunization , beta (programming language) , antibody , genetically modified mouse , amyloid precursor protein secretase , amyloid beta , amyloid precursor protein , astrocyte , immunology , medicine , amyloid (mycology) , transgene , alzheimer's disease , gamma secretase , disease , chemistry , inflammation , central nervous system , pathology , biochemistry , gene , computer science , programming language
Memapsin 2 (β‐secretase, BACE1) is the protease that initiates cleavage of β‐amyloid precursor protein leading to the production of amyloid‐β (Aβ) and the onset of Alzheimer's disease (AD). Reducing Aβ by targeting memapsin 2 is a major strategy in developing new AD therapy. Here, in a proof‐of‐con‐cept study, we show that immunization of transgenic AD mice (Tg2576) with memapsin 2 resulted in Aβ reduction and cognitive improvement. To study the basis of this therapy, we demonstrated that anti‐memap‐sin 2 (anti‐M2) antibodies were rapidly internalized and reduced Aβ 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 Aβ 40 and Aβ 42 (~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 Aβ 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. FASEB J. 21, 3184–3196 (2007)