Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease
Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease
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DOI：
10.1093/brain/awu213
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发表时间：
2014-10-01
期刊：
影响因子：
14.5
通讯作者：
Grueninger, Fiona
中科院分区：
文献类型：
--
作者：
Collin, Ludovic;Bohrmann, Bernd;Grueninger, Fiona
阿尔茨海默病患者脑组织tau病变的严重程度与疾病进展密切相关。因此，tau免疫疗法已被提出作为治疗阿尔茨海默病的一种新方法，并通过tau转基因小鼠的主动或被动免疫获得了令人鼓舞的结果。这项工作研究了免疫治疗影响tau病理的机制。我们在阿尔茨海默病的三重转基因小鼠模型中证明了类似阿尔茨海默病的tau病理的发展，并表明tau/pS422存在于神经细胞表面的膜微域中。长期外周应用抗tau/pS422抗体可减少tau病理堆积。抗tau/pS422抗体在神经元和溶酶体中的存在是明确的。我们认为，抗tau/pS422抗体结合到膜相关的tau/pS422上，抗原-抗体复合体在细胞内被清除，从而为tau免疫治疗如何改善神经元tau病理提供了一种解释。
The severity of tau pathology in Alzheimer's disease brain correlates closely with disease progression. Tau immunotherapy has therefore been proposed as a new therapeutic approach to Alzheimer's disease and encouraging results have been obtained by active or passive immunization of tau transgenic mice. This work investigates the mechanism by which immunotherapy can impact tau pathology. We demonstrate the development of Alzheimer's disease-like tau pathology in a triple transgenic mouse model of Alzheimer's disease and show that tau/pS422 is present in membrane microdomains on the neuronal cell surface. Chronic, peripheral administration of anti-tau/pS422 antibody reduces the accumulation of tau pathology. The unequivocal presence of anti-tau/pS422 antibody inside neurons and in lysosomes is demonstrated. We propose that anti-tau/pS422 antibody binds to membrane-associated tau/pS422 and that the antigen-antibody complexes are cleared intracellularly, thereby offering one explanation for how tau immunotherapy can ameliorate neuronal tau pathology.