Autoantibody-catalyzed hydrolysis of amyloid β peptide
Autoantibody-catalyzed hydrolysis of amyloid β peptide
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DOI：
10.1074/jbc.m707983200
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发表时间：
2008-02-22
影响因子：
4.8
通讯作者：
Paul, Sudhir
中科院分区：
文献类型：
--
作者：
Taguchi, Hiroaki;Planque, Stephanie;Paul, Sudhir
我们描述了能降解淀粉样β蛋白1-40(Aβ40)的IgM类人类自身抗体。来自Waldenstrom巨球蛋白血症患者的单抗IgM在Lys-28-Gly-29和Lys-16-Ala-17键上水解Aβ40。亲电丝氨酸蛋白酶抑制剂按化学计量比抑制该酶的催化活性。用催化型IgM处理可阻断Aβ40在神经细胞培养中的聚集和毒性。从阿尔茨海默病(AD)患者血清中提纯的IgM对Aβ40的水解率高于年龄匹配的非痴呆症患者的IgM。来自非老年人的免疫球蛋白表达的催化活性最低。在外周循环中发现的生理Aβ和IgM浓度下，反应速度足以提供可察觉的降解。阿尔茨海默病大脑中Aβ浓度的增加被认为会导致神经退行性变化。外周注射Aβ结合抗体已被认为是治疗AD的一种潜在方法。我们的结果表明，催化型IgM自身抗体可以帮助清除Aβ，并为将催化型抗体用于AD免疫治疗打开了可能性。
We describe IgM class human autoantibodies that hydrolyze amyloid beta peptide 1-40 (A beta 40). A monoclonal IgM from a patient with Waldenstrom's macroglobulinemia hydrolyzed A beta 40 at the Lys-28 -Gly-29 bond and Lys-16 - Ala-17 bonds. The catalytic activity was inhibited stoichiometrically by an electrophilic serine protease inhibitor. Treatment with the catalytic IgM blocked the aggregation and toxicity of A beta 40 in neuronal cell cultures. IgMs purified from the sera of patients with Alzheimer disease (AD) hydrolyzed A beta 40 at rates superior to IgMs from age-matched humans without dementia. IgMs from non-elderly humans expressed the least catalytic activity. The reaction rate was sufficient to afford appreciable degradation at physiological A beta and IgM concentrations found in peripheral circulation. Increased A beta concentrations in the AD brain are thought to induce neurodegenerative effects. Peripheral administration of A beta binding antibodies has been suggested as a potential treatment of AD. Our results suggest that catalytic IgM autoantibodies can help clear A beta, and they open the possibility of using catalytic Abs for AD immunotherapy.