Table 1_Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease.xlsx

IntroductionIndividuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer’s disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry.
MethodsWe combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity.
ResultsThe hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD.
ConclusionsThese cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development.

### 引言
唐氏综合征（Down syndrome, DS）患者终生都会出现神经功能缺陷，包括阿尔茨海默病（Alzheimer’s disease, AD）病理特征的形成以及认知功能受损。在细胞层面，对唐氏综合征/阿尔茨海默病（DS/AD）的死后人类脑组织及小鼠模型的研究中，均观察到神经元基因表达失调现象。截至目前，针对唐氏综合征患者海马神经元基因表达的RNA测序（RNA-sequencing, RNA-seq）分析，包括对基于离散神经环路的连接特征的解析，仍是一项重大的研究空白。我们推测，具有空间定位特征的海马神经元会呈现独特的基因表达模式，这在一定程度上源于内在神经环路完整性的功能异常。
### 方法
本研究将激光捕获显微切割（laser capture microdissection）用于微量分离单个神经元群体，并结合单群体RNA测序分析，对海马（大脑中与学习、记忆及突触活动密切相关的脑区）内的CA1、CA3锥体神经元以及齿状回颗粒细胞进行基因表达分析。
### 结果
在Ts65Dn唐氏综合征/阿尔茨海默病小鼠模型中，海马体呈现年龄依赖性的神经退行性病变，病变起始于小鼠约6月龄时。在Ts65Dn小鼠体内，每一类兴奋性海马神经元均表现出独特的基因表达改变。生物信息学分析揭示了独特的易损性特征及差异，这些发现与该唐氏综合征/阿尔茨海默病模型中神经退行性病变的发生具有机制层面的关联。
### 结论
这些神经元亚型特异性的易损性可能是退行性内表型的潜在基础，这提示我们可以针对特定神经元群体开展精准医学研究，以推动合理的治疗方案开发。