Frontotemporal lobar degeneration-related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus
Frontotemporal lobar degeneration-related proteins induce only subtle memory-related deficits when bilaterally overexpressed in the dorsal hippocampus
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DOI：
10.1016/j.expneurol.2011.12.002
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发表时间：
2012-02-01
影响因子：
5.3
通讯作者：
Klein, Ronald L.
中科院分区：
文献类型：
--
作者：
Dayton, Robert D.;Wang, David B.;Klein, Ronald L.
额颞叶变性（FTLD）是一种涉及认知能力下降和痴呆的神经退行性疾病。为了模拟MD和其他tau和TDP-43蛋白病中发生的海马神经变性和记忆相关行为障碍，我们使用腺相关病毒血清型9 （AAV9）载体在成年大鼠海马背侧诱导微管相关蛋白tau或交互反应DNA结合蛋白43 kDa （TDP-43）的双侧表达。表达人野生型tau或TDP-43。载体/剂量设计为神经元内的中等表达水平。在基因转移12周后，评估大鼠在Morris水任务中的获取和保留情况。与对照组相比，两个矢量都没有改变采集性能。在保留测量中，TDP-43组存在损伤。组织学检查显示，TDP-43组注射部位近端齿状回颗粒细胞特异性丢失，伴胶质增生，海马背侧萎缩。尽管有特定的tau病理，但令人惊讶的是，tau基因转移并没有引起明显的神经元丧失或行为障碍。数据表明，TDP-43在大鼠中产生轻度行为障碍和海马神经变性，而tau则没有。该模型可用于研究FTLD及其他与海马tau和TDP-43病理相关的疾病（包括阿尔茨海默病）的机制，并与早期轻度损伤相关。(C) 2011爱思唯尔公司版权所有。
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that involves cognitive decline and dementia. To model the hippocampal neurodegeneration and memory-related behavioral impairment that occurs in MD and other tau and TDP-43 proteinopathy diseases, we used an adeno-associated virus serotype 9 (AAV9) vector to induce bilateral expression of either microtubule-associated protein tau or transactive response DNA binding protein 43 kDa (TDP-43) in adult rat dorsal hippocampus. Human wild-type forms of tau or TDP-43 were expressed. The vectors/doses were designed for moderate expression levels within neurons. Rats were evaluated for acquisition and retention in the Morris water task over 12 weeks after gene transfer. Neither vector altered acquisition performance compared to controls. In measurements of retention, there was impairment in the TDP-43 group. Histological examination revealed specific loss of dentate gyrus granule cells and concomitant gliosis proximal to the injection site in the TDP-43 group, with shrinkage of the dorsal hippocampus. Despite specific tau pathology, the tau gene transfer surprisingly did not cause obvious neuronal loss or behavioral impairment. The data demonstrate that TDP-43 produced mild behavioral impairment and hippocampal neurodegeneration in rats, whereas tau did not. The models could be of value for studying mechanisms of FTLD and other diseases with tau and TDP-43 pathology in the hippocampus including Alzheimer's disease, with relevance to early stage mild impairment. (C) 2011 Elsevier Inc. All rights reserved.