Expression Profile Analysis of Vulnerable CA1 Pyramidal Neurons in Young-Middle-Aged Ts65Dn Mice
Expression Profile Analysis of Vulnerable CA1 Pyramidal Neurons in Young-Middle-Aged Ts65Dn Mice
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DOI：
10.1002/cne.23663
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发表时间：
2015-01-01
影响因子：
2.5
通讯作者：
Ginsberg, Stephen D.
中科院分区：
文献类型：
--
作者：
Alldred, Melissa J.;Lee, Sang Han;Ginsberg, Stephen D.
唐氏综合征（DS）是智力残疾（ID）的最常见原因。患有DS的个体表现出各种认知缺陷，最显著的是在海马学习和记忆中，并且表现出阿尔茨海默病（AD）的病理学特征，具有胆碱能基底前脑（CBF）神经元的神经变性。通过在相关动物模型（称为Ts 65 Dn小鼠）中进行基因表达分析，对神经病理学的分子和细胞基础进行了阐明。Ts 65 Dn小鼠是DS的节段性三体模型，其模拟DS/AD病理学，特别是年龄相关的认知功能障碍和基底前脑胆碱能神经元（BFCN）的变性。为了确定表达水平的变化，在BFCN变性开始时，在成年（4-9月龄）Ts 65 Dn小鼠中进行角氨1（CA 1）锥体神经元的分子指纹分析。为了定量在此早期时间段期间的转录组学变化，进行激光捕获显微切割（LCM）、末端连续（TC）RNA扩增、定制设计的微阵列分析以及随后通过qPCR和经由免疫印迹的蛋白质分析对个体转录物的验证。结果表明，与正常的二体（2N）同窝仔相比，Ts 65 Dn小鼠的CA 1锥体神经元内的显著改变，特别是在与神经变性相关的其他类别的转录物中的神经营养因子及其同源神经营养因子受体的下调中。在三体小鼠模型中隔海马缺陷时，这种单群体基因表达分析的结果揭示了一个脆弱的回路，该回路可能导致在DS中总是可见的AD样病理学，这可能有助于确定变性机制，并为治疗干预提供新的基因靶点。J. Comp.神经元523：61-74，2015. (c)2014 Wiley Periodicals，Inc.
Down syndrome (DS) is the most prevalent cause of intellectual disability (ID). Individuals with DS show a variety of cognitive deficits, most notably in hippocampal learning and memory, and display pathological hallmarks of Alzheimer's disease (AD), with neurodegeneration of cholinergic basal forebrain (CBF) neurons. Elucidation of the molecular and cellular underpinnings of neuropathology has been assessed via gene expression analysis in a relevant animal model, termed the Ts65Dn mouse. The Ts65Dn mouse is a segmental trisomy model of DS that mimics DS/AD pathology, notably age-related cognitive dysfunction and degeneration of basal forebrain cholinergic neurons (BFCNs). To determine expression level changes, molecular fingerprinting of cornu ammonis 1 (CA1) pyramidal neurons was performed in adult (4-9 month-old) Ts65Dn mice, at the initiation of BFCN degeneration. To quantitate transcriptomic changes during this early time period, laser capture microdissection (LCM), terminal continuation (TC) RNA amplification, custom-designed microarray analysis, and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting was performed. The results indicate significant alterations within CA1 pyramidal neurons of Ts65Dn mice compared with normal disomic (2N) littermates, notably in the downregulation of neurotrophins and their cognate neurotrophin receptors among other classes of transcripts relevant to neurodegeneration. The results of this single-population gene expression analysis at the time of septohippocampal deficits in a trisomic mouse model shed light on a vulnerable circuit that may cause the AD-like pathology invariably seen in DS that could help to identify mechanisms of degeneration, and provide novel gene targets for therapeutic interventions. J. Comp. Neurol. 523:61-74, 2015. (c) 2014 Wiley Periodicals, Inc.