Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA.
Exp Neurol. 2012 May;235(1):297-305. doi: 10.1016/j.expneurol.2012.02.011. Epub 2012 Feb 28.
The transactivation DNA-binding protein (TDP-43) pathology is associated with fronto-temporal lobar dementia (FTLD) with ubiquitinated inclusions and some cases of Alzheimer's disease (AD). Proteolytic fragments of β-amyloid precursor protein (βAPP) are detected in AD as well as the cerebrospinal fluid (CSF) from FTLD and Amyotrophic Lateral Sclerosis (ALS) patients, suggesting alteration in APP processing. Because of the overlap in TDP-43 pathology between FTLD and AD, we sought to determine whether there is a relationship between TDP-43 and APP metabolism. We generated gene transfer models using lentiviral delivery of human TDP-43 and Aβ(1-42) into the rat primary motor cortex and examined their role 2 weeks post-injection. Expression of TDP-43 and/or Aβ(1-42) increase pro-inflammatory markers, including Interleukin (IL)-6, tumor necrosis factor (TNF-α), glial neurofibrillary proteins (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1). Lentiviral Aβ(1-42) up-regulates endogenous TDP-43 and promotes its phosphorylation, aggregation and cleavage into 35 kDa fragments. Inversely, lentiviral TDP-43 expression increases the levels and activity of β-secretase (BACE), accelerating production of APP C-terminal fragments (C99) and Aβ(1-40). Here we show that TDP-43 up-regulates APP metabolism and suggest a mechanistic link between TDP-43 and BACE.
转激活 DNA 结合蛋白（TDP-43）病理学与额颞叶痴呆（FTLD）伴泛素化包含体和一些阿尔茨海默病（AD）有关。β-淀粉样前体蛋白（βAPP）的蛋白水解片段在 AD 中以及 FTLD 和肌萎缩侧索硬化症（ALS）患者的脑脊液（CSF）中均有检测到，表明 APP 加工发生改变。由于 TDP-43 病理学在 FTLD 和 AD 之间存在重叠，我们试图确定 TDP-43 是否与 APP 代谢之间存在关系。我们使用慢病毒传递将人 TDP-43 和 Aβ（1-42）递送至大鼠初级运动皮层，建立基因转移模型，并在注射后 2 周检查其作用。TDP-43 和/或 Aβ（1-42）的表达增加促炎标志物，包括白细胞介素（IL）-6、肿瘤坏死因子（TNF-α）、神经胶质神经丝蛋白（GFAP）和钙结合接头分子 1（IBA-1）。慢病毒 Aβ（1-42）上调内源性 TDP-43 并促进其磷酸化、聚集和切割成 35 kDa 片段。相反，慢病毒 TDP-43 表达增加β-分泌酶（BACE）的水平和活性，加速 APP C 端片段（C99）和 Aβ（1-40）的产生。在这里，我们表明 TDP-43 上调 APP 代谢，并提出 TDP-43 和 BACE 之间的机制联系。
