BACKGROUND: Over the past few years, amyloid beta protein (Abeta) vaccination has become one of the most effective treatments for Alzheimer's disease. However, the appearance of severe side effects during clinical trials has highlighted the need for improved safety and efficacy. Although antibodies directed against the amino (N)-termini of Abeta are highly effective for passive immunization, a substantial risk of inducing cerebral hemorrhage has been documented. OBJECTIVE: We investigated the effect of the administration of BC05, which was the first antibody developed against the carboxyl (C)-termini of Abeta42(43), on the clearance of brain Abeta42(43). METHOD: The BC05 antibody was injected into the peritoneal cavity of Tg2576 transgenic mice expressing betaAPP(KM670/671NL) once a week from 3 to 12 months of age. RESULTS: BC05 caused a selective 44-fold increase in plasma Abeta42(43) and a significant increase in brain soluble Abeta42(43), showing a 156% difference. Brain insoluble Abeta40 and Abeta42(43) levels were decreased by 27.3 and 31.5%, respectively. A reduction in the number of BAN50-labeled plaques was observed. CONCLUSIONS: BC05 might render Abeta42(43) soluble within the brain and inhibit the insoluble deposition of Abeta40 and Abeta42(43). By analyzing the mechanism of the elevation of soluble Abeta42(43) after passive immunization of BC05, safer and more effective methods of immunotherapy for Alzheimer's disease might be developed.
BACKGROUND: Over the past few years, amyloid beta protein (Abeta) vaccination has become one of the most effective treatments for Alzheimer's disease. However, the appearance of severe side effects during clinical trials has highlighted the need for improved safety and efficacy. Although antibodies directed against the amino (N)-termini of Abeta are highly effective for passive immunization, a substantial risk of inducing cerebral hemorrhage has been documented. OBJECTIVE: We investigated the effect of the administration of BC05, which was the first antibody developed against the carboxyl (C)-termini of Abeta42(43), on the clearance of brain Abeta42(43). METHOD: The BC05 antibody was injected into the peritoneal cavity of Tg2576 transgenic mice expressing betaAPP(KM670/671NL) once a week from 3 to 12 months of age. RESULTS: BC05 caused a selective 44-fold increase in plasma Abeta42(43) and a significant increase in brain soluble Abeta42(43), showing a 156% difference. Brain insoluble Abeta40 and Abeta42(43) levels were decreased by 27.3 and 31.5%, respectively. A reduction in the number of BAN50-labeled plaques was observed. CONCLUSIONS: BC05 might render Abeta42(43) soluble within the brain and inhibit the insoluble deposition of Abeta40 and Abeta42(43). By analyzing the mechanism of the elevation of soluble Abeta42(43) after passive immunization of BC05, safer and more effective methods of immunotherapy for Alzheimer's disease might be developed.
Authors: Yona Levites; Pritam Das; Robert W Price; Marjorie J Rochette; Lisa A Kostura; Eileen M McGowan; Michael P Murphy; Todd E Golde Journal: J Clin Invest Date: 2005-12-08 Impact factor: 14.808
Authors: Kiran Yanamandra; Tirth K Patel; Hong Jiang; Suzanne Schindler; Jason D Ulrich; Adam L Boxer; Bruce L Miller; Diana R Kerwin; Gilbert Gallardo; Floy Stewart; Mary Beth Finn; Nigel J Cairns; Philip B Verghese; Ilana Fogelman; Tim West; Joel Braunstein; Grace Robinson; Jennifer Keyser; Joseph Roh; Stephanie S Knapik; Yan Hu; David M Holtzman Journal: Sci Transl Med Date: 2017-04-19 Impact factor: 17.956