Amyloid-beta reduction by memapsin 2 (beta-secretase) immunization.
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.
Chang
Wan-Pin
WP
Protein Studies Program, Oklahoma Medical Research Foundation, 825 N.E. 13th St., Oklahoma City, OK 73104, USA. wanpin-chang@omrf.ouhsc.edu
Downs
Deborah
D
Huang
Xiang-Ping
XP
Da
Huining
H
Fung
Kar-Ming
KM
Tang
Jordan
J
D000367:Age Factors; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D007114:Immunization; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000906:Antibodies; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human