AD-BXD Mouse PreFrontal Cortex Proteomics

The AD-BXD mouse population is a powerful emerging model for studying AD resilience. AD-BXD mice query two different levels of genetic information: genometypes and genotypes. The genetically diverse BXD genometypes are a mosaic of the approximately 6 million segregating single nucleotide polymorphisms between C57BL/6J and DBA/2J mice. The transgenic genotype of the 5 times familial Alzheimer’s disease (5xFAD) transgene, which includes human APP carrying three pathogentic variants and human PSEN1 carrying two pathogenic, can be contrasted with non-transgenic control animals (Ntg). Reproducible BXD genometypes allow repeated measurement of the same mosaic genomes, a strategy that boosts the mappable heritability of genetic loci (cite ). This property facilitates QTL mapping of the relatively lower effect size variants that modify susceptibility to Alzheimer’s-like cognitive phenotypes in 5xFAD animals. Further, the same cognitive phenotype can be measured in both 5xFAD and Ntg mice within the same genometype. The ability to contrast a genometype’s performance with different AD genotypes facilitates the measurement of novel and interesting derived phenotypes based upon the property of trait correlation (cite ). Because of these properties, our lab has successfully leveraged AD-BXD mice to identify genetic modifiers of AD-related phenotypes in recent years.
We quantified resilience using a novel regression-based metric. We utilized this measure to map resilience to a locus, then leveraged proteomics data to identify a putative molecular mechanism for the genetic resilience factor. We found potential novel targets for AD by querying elements coregulated in trans to the putative molecular mechanism. Finally, we implicated differential expression of networked synaptic proteins as the likeliest downstream consequences of differences in resilience.

AD-BXD小鼠种群是极具潜力的阿尔茨海默病（Alzheimer’s Disease, AD）抗性研究新兴模型。AD-BXD小鼠可从两个维度探究遗传信息：基因组型（genometype）与基因型（genotype）。遗传背景多样的BXD基因组型，由C57BL/6J与DBA/2J小鼠之间约600万个分离单核苷酸多态性（single nucleotide polymorphisms, SNPs）镶嵌构成。携带3个致病突变的人类APP基因与携带2个致病突变的人类PSEN1基因的5倍家族性阿尔茨海默病（5xFAD）转基因基因型，可与非转基因对照动物（Ntg）形成有效对照。可重复获取的BXD基因组型允许对同一镶嵌基因组进行重复测定，该策略可提升遗传位点的可定位遗传力（cite）。这一特性可支持对效应量相对较低的变异开展数量性状位点（QTL）定位，这类变异可调控5xFAD小鼠阿尔茨海默病样认知表型的易感性。此外，在同一基因组型背景下，可同时在5xFAD与Ntg小鼠中测定相同的认知表型。通过对比同一基因组型在不同AD基因型下的表型表现，可基于性状相关性特征挖掘新颖且具有研究价值的衍生表型（cite）。依托上述特性，本课题组近年来已成功利用AD-BXD小鼠鉴定出AD相关表型的遗传修饰因子。
我们采用一种基于回归分析的新型量化指标对AD抗性进行了定量评估。利用该指标，我们将AD抗性位点进行了定位，并结合蛋白质组学（proteomics）数据为该遗传抗性因子推定了潜在分子机制。通过查询与该推定分子机制存在反式共调控关系的基因组元件，我们发现了潜在的AD新型治疗靶点。最终，我们推断网络化突触蛋白的差异表达是抗性差异最可能的下游效应。