Karlnoski Rachel A, Rosenthal Arnon, Alamed Jennifer, Ronan Victoria, Gordon Marcia N, Gottschall Paul E, Grimm Jan, Pons Jaume, Morgan Dave
School of Basic Biomedical Sciences, Department of Molecular Pharmacology and Physiology, Alzheimer's Research Laboratory, University of South Florida, 12901 Bruce B Downs Blvd, MDC Box 8, Tampa, FL 33612-4799, USA.
J Neuroimmune Pharmacol. 2008 Sep;3(3):187-97. doi: 10.1007/s11481-008-9114-6. Epub 2008 Jul 8.
Anti-Abeta antibody administration to amyloid-depositing transgenic mice can reverse amyloid pathology and restore memory function. However, in old mice, these treatments also increase vascular leakage and promote formation of vascular amyloid deposits. Deglycosylated antibodies with reduced affinity for Fcgamma receptors and complement are associated with reduced vascular amyloid and microhemorrhage while retaining amyloid-clearing and memory-enhancing properties of native intact antibodies. In the current experiment, we investigated the effect of 3, 10, or 30 mg/kg of deglycosylated antibody (D-2H6) on amyloid pathology and cognitive behavior in old Tg2576 mice. We found that low doses of deglycosylated antibody appear more efficacious than higher doses in reducing pathology and memory loss in amyloid precursor protein (APP) transgenic mice. These data suggest that excess antibody unbound to antigen can interfere with antibody-mediated Abeta clearance, possibly by saturating the FcRn antibody transporter.
向淀粉样蛋白沉积转基因小鼠施用抗淀粉样前体蛋白（Aβ）抗体可逆转淀粉样蛋白病理并恢复记忆功能。然而，在老年小鼠中，这些治疗也会增加血管渗漏并促进血管淀粉样蛋白沉积物的形成。对Fcγ受体和补体亲和力降低的去糖基化抗体与减少的血管淀粉样蛋白和微出血相关，同时保留天然完整抗体的淀粉样蛋白清除和记忆增强特性。在当前实验中，我们研究了3、10或30mg/kg去糖基化抗体（D-2H6）对老年Tg2576小鼠淀粉样蛋白病理和认知行为的影响。我们发现，低剂量的去糖基化抗体在减少淀粉样前体蛋白（APP）转基因小鼠的病理和记忆丧失方面似乎比高剂量更有效。这些数据表明，未与抗原结合的过量抗体可能会通过使FcRn抗体转运体饱和来干扰抗体介导的Aβ清除。
