Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome
Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome
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DOI：
10.1016/j.neuron.2004.07.003
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发表时间：
2004-08-05
期刊：
影响因子：
16.2
通讯作者：
LaFerla, FM
中科院分区：
文献类型：
--
作者：
Oddo, S;Billings, L;LaFerla, FM
β淀粉样蛋白（Abeta）斑块和神经元缠结是阿尔茨海默病（AD）的标志性神经病理学病变。使用在AD相关脑区域中发展两种病变的三重转基因模型（3xTg-AD），我们确定了Abeta清除对tau病理学发展的后果。在这里，我们表明AD免疫疗法不仅减少细胞外Abeta斑块，而且减少细胞内Abeta积聚，最显著的是导致早期tau病理的清除。我们发现Abeta沉积物首先被清除，随后在tau病理学之前重新出现，表明AD和tau之间存在分层和直接关系。tau病变的清除由蛋白酶体介导，并且取决于tau的磷酸化状态，因为过度磷酸化的tau聚集体不受Abeta抗体处理的影响。这些发现表明，Abeta免疫可能有助于清除AD的两个标志性病变，前提是在疾病过程的早期进行干预。
Amyloid-beta (Abeta) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimer's disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of Abeta clearance on the development of tau pathology. Here we show that AD immunotherapy reduces not only extracellular Abeta plaques but also intracellular Abeta accumulation and most notably leads to the clearance of early tau pathology. We find that Abeta deposits are cleared first and subsequently reemerge prior to the tau pathology, indicative of a hierarchical and direct relationship between AD and tau. The clearance of the tau pathology is mediated by the proteasome and is dependent on the phosphorylation state of tau, as hyperphosphorylated tau aggregates are unaffected by the Abeta antibody treatment. These findings indicate that Abeta immunization may be useful for clearing both hallmark lesions of AD, provided that intervention occurs early in the disease course.