Wild type TDP-43 induces neuro-inflammation and alters APP metabolism in lentiviral gene transfer models

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• 作者：Alexander M. Herman ; Preeti J. Khandelwal ; G. William Rebeck ; Charbel E.-H. Moussa ; ^{cem46@georgetown.edu}
• 关键词：TDP-43 ; Tar DNA binding protein ; A尾 ; 尾-amyloid ; FTLD ; fronto-temporal lobar dementia ; ALS ; amyotrophic lateral sclerosis ; Lv ; lentivirus ; GFAP ; glial neurofibrillary proteins ; IBA-1 ; ionized calcium binding adaptor molecule 1 ; TNF-伪 ; tumor necrosis fac
• 刊名：Experimental Neurology
• 出版年：2012
• 期刊代码：78_00144886
• 类别：neu
• 出版时间：May, 2012
• 卷：235
• 期：1
• 页码：297-305
• 文件大小：1619 K

摘要

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 尾-amyloid precursor protein (尾APP) 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 A尾_1-42 into the rat primary motor cortex and examined their role 2 weeks post-injection. Expression of TDP-43 and/or A尾_1-42 increase pro-inflammatory markers, including Interleukin (IL)-6, tumor necrosis factor (TNF-伪), glial neurofibrillary proteins (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1). Lentiviral A尾_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 尾-secretase (BACE), accelerating production of APP C-terminal fragments (C99) and A尾_1-40. Here we show that TDP-43 up-regulates APP metabolism and suggest a mechanistic link between TDP-43 and BACE.