Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: Their relation to AD common pathology
Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: Their relation to AD common pathology
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DOI：
10.1111/j.1440-1789.2009.01017.x
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发表时间：
2009-10-01
期刊：
影响因子：
2.3
通讯作者：
Okamoto, Koichi
中科院分区：
文献类型：
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作者：
Kadokura, Ai;Yamazaki, Tsuneo;Okamoto, Koichi
最初，反式激活反应区(TAR)-DNA结合蛋白43(TDP-43)被认为是泛素阳性包涵体(FTLD-U)和肌萎缩侧索硬化症(ALS)患者脑内泛素阳性包涵体和tau阴性包涵体的疾病特异性成分；然而，现在人们普遍知道，在其他神经退行性疾病中，该蛋白也异常聚集在神经元中。根据主要在内侧颞叶的观察，在20-30%的阿尔茨海默病(AD)脑中检测到TDP-43免疫反应神经元包涵体。然而，这些病例是否代表一种混合性疾病，即AD/FTLD-U混合型，仍存在争议。为了解决这个问题，有必要获得更多关于TDP-43免疫反应性的区域分布以及它与AD常见病理的关系的知识。在这里，我们描述了5/16例AD患者内侧颞叶TDP-43免疫反应异常(31%)。大部分沉积为胞质内包涵体，主要位于下丘脑回和海马旁回，少数见于海马齿状颗粒细胞。TDP-43阳性包涵体和老年斑/神经原纤维缠结的分布并不总是一致的，TDP-43和磷酸化tau在细胞内的共定位也很少见。内侧颞叶有TDP-43阳性包涵体的病例，额叶也有异常高密度的TDP-43免疫反应，而顶叶和枕叶未见。在细胞内，TDP-43阳性包涵体高度泛素化，并与p62免疫反应共存。我们的发现表明，TDP-43的异常沉积和AD的病理(老年斑和神经原纤维缠结的形成)可能是独立发生的。然而，结合以往报道的结果，TDP-43免疫反应在AD患者的海马区和额叶皮质的分布似乎是不同的。我们认为，现在确定TDP-43积聚是AD病理的一部分还是完全独立的病理所致还为时过早。
Initially, trans activation responsive region (TAR)-DNA-binding protein 43 (TDP-43) was considered to be a disease-specific component of ubiquitin-positive and tau-negative inclusions in the brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS); however, it is now widely known that this protein also abnormally accumulates in neurons in other neurodegenerative diseases. On the basis of observation mainly in the medial temporal lobe, TDP-43-immunoreactive neuronal inclusions have been detected in 20-30% of Alzheimer disease (AD) brains. However, it is controversial whether these cases represent a combined disease, that is, mixed AD/FTLD-U. To address this issue, it is necessary to obtain more knowledge on the region-specific distribution of TDP-43 immunoreactivity and also about its relationship to AD common pathology. Here, we describe abnormal TDP-43 immunoreactivity in the medial temporal lobe in 5/16 AD patients (31%). Most of the depositions were cytoplasmic inclusions, mainly located in the subiculum and parahippocampal gyrus and rarely in dentate granular cells of the hippocampus. TDP-43-positive inclusions and senile plaque/neurofibrillary tangle distribution were not always identical, and intracellular colocalizations of TDP-43 and phospho-tau were also infrequent. The cases showing TDP-43-positive inclusions in the medial temporal lobe also showed abnormally highly dense TDP-43 immunoreactivity in the frontal, but not in the parietal and occipital cortices. Intracellularly, TDP-43-positive inclusions were highly ubiquitinated and colocalized with p62 immunoreactivity as well. Our findings suggest that abnormal TDP-43 deposition and AD pathology (formation of senile plaques and neurofibrillary tangles) might occur independently. However, taken together with the results of previous reports, the distribution of TDP-43 immunoreactivity in the hippocampus and frontal cortex in AD appear to be varying. We consider that it is still too early to determine that the TDP-43 accumulation is a part of AD pathology or result from a completely independent pathology.