beneficial effect of antibodies against β- secretase cleavage site of app on alzheimer’s-like pathology in triple-transgenic mice抗体产生的有利影响β-分泌酶裂解位点的应用在它们老年痴呆病理triple-transgenic老鼠.pdfVIP

Beneficial Effect of Antibodies against b- Secretase Cleavage Site of App on Alzheimer’s-Like Pathology in Triple-Transgenic Mice Inna Rabinovich-Nikitin, Idan S. Rakover, Maria Becker, Beka Solomon* Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel Abstract The toxicity of amyloid b and tau, the two hallmark proteins in Alzheimer’s disease (AD), has been extensively studied individually. Recently new data suggest their possible interactions and synergistic effects in the disease. In this study, we investigate the ability of antibodies against the b secretase cleavage site on APP, named BBS1, to affect tau pathology, besides their well established effect on intracellular Ab and amyloid load. For this purpose we treated the triple transgenic mice model of AD (3x Tg-AD) with mAb BBS1 intracerebroventricularly, using mini osmotic pumps for one month. The experimental data demonstrated reduction in total and phosphorylated tau levels, explained by significant reduction in GSK3b which phosphorylates tau on sites recognized by antibodies against PHF1 and AT-8. The treatment increased the cognitive capabilities and reduced the brain inflammation levels which accompany AD pathology. The data showing that tau pathology was significantly reduced by BBS1 antibodies suggest a close interaction between tau and Ab in the development of AD, and may serve as an efficient novel immunotherapy against both hallmarks of this disease. Citation: Rabinovich-Nikitin I, Rakover IS, Becker M, Solomon B (2012) Beneficial Effect of Antibodies against b- Secretase Cleavage Site of App on Alzheimer’s- Like Pathology in Triple-Transgenic Mice. PLoS ONE 7(10): e46650. doi:10.1371/journal.pone.0046650 Editor: Joseph El Khoury, Massachusetts General Hospital