Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies
Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies
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DOI：
10.1007/s00401-008-0480-1
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发表时间：
2009-02-01
影响因子：
12.7
通讯作者：
Akiyama, Haruhiko
中科院分区：
文献类型：
--
作者：
Arai, Tetsuaki;Mackenzie, Ian R. A.;Akiyama, Haruhiko
磷酸化和蛋白水解裂解的TDP-43是最常见的病理亚型额颞叶变性（FTLD-U）中泛素阳性包涵体的主要成分。在患有其他痴呆症的患者亚群中观察到TDP-43的细胞内积累，包括阿尔茨海默病（AD）和路易体痴呆（DLB）。然而，TDP-43病理学在这些疾病中的病理学意义是未知的，因为在AD和DLB脑中积累的TDP-43的生化特征，特别是其磷酸化位点和片段化模式，仍然不清楚。为了解决这些问题，我们使用磷酸化依赖性抗TDP-43抗体对AD和DLB病例进行了免疫组织化学和生化分析。我们发现AD（36-56%）和DLB（53-60%）中病理性TDP-43的频率高于先前报道的频率。在TDP-43阳性病例中，约20-30%显示新皮质TDP-43病理学类似于与颗粒蛋白前体基因（PGRN）突变相关的FTLD-U亚型。免疫印迹分析的sarkosyl不溶性馏分与新皮质TDP-43病理的情况下，显示了强烈的染色的几个低分子量的带，对应的TDP-43的C-末端片段。有趣的是，AD和DLB中这些C-末端片段的带型也对应于先前在与PGRN突变相关的FTLD-U亚型中观察到的带型。这些结果表明，TDP-43病理的形态学和生化特征在AD或DLB与FTLD-U的特定亚型之间是共同的。可能存在遗传因素，例如PGRN的突变或遗传变体，其是TDP-43、tau和α-突触核蛋白异常沉积共同发生的基础。
Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a subpopulation of patients with other dementia disorders, including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36-56%) and in DLB (53-60%) than previously reported. Of the TDP-43-positive cases, about 20-30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and alpha-synuclein.