Role of the TOMM40 poly-T variant in the pathogenesis of Alzheimer's disease

描述（由申请人提供）：我们已经证明TOMM40多态性多t变异与晚发性阿尔茨海默病（AD）发病年龄之间存在很强的相关性。对于发生AD的APOE e3/4患者，与APOE e3相关的多t重复序列较长的患者比与APOE e3相关的多t多态性较短的患者平均早7年发生AD。我们在一个不同的人群中重复了这一发现。在APOE e3/e3纯合子中，poly-T变体的长度与灰质密度之间也存在显著的相关性，这与APOE e4无关。TOMM40与APOE处于连锁不平衡状态，编码线粒体外膜转座酶蛋白。我们的中心假设是，多t通道控制大脑中TOMM40和APOE的表达，从而调节这些蛋白质参与的途径。我们将在基因组、基因和生化水平上检验这一假设。我们将精确识别长、短和祖先的多t束，并将AD发病年龄和AD风险与这些等位基因联系起来。我们将通过测量快速解剖的人脑样本中的APOE和TOMM40 mRNA和蛋白水平来测试我们的工作模型，即多t通道调节TOMM40和APOE的表达，并将这些变化与不同大脑区域对ad相关损伤的易感性联系起来。我们还将构建两个人类小鼠模型的TOMM40-APOE连锁不平衡区域，这将允许更详细的，基于机制的研究这些基因的表达调节。我们将小鼠的TOMM4-APOE连锁不平衡区与人类的同源区域交换。两个模型都将对人类APOE e3进行纯合，从而消除APOE e4可能的混杂效应，我们将对短型多态t进行纯合，而对长型多态t进行纯合。成功实现这些目标将促进我们对阿尔茨海默病遗传风险因素的分子机制的理解，并将为开发有效的晚发性阿尔茨海默病预防治疗提供有价值的途径。

DESCRIPTION (provided by applicant): We have demonstrated that there is a strong association between polymorphic poly-T variant of TOMM40 and the age of onset of late-onset Alzheimer's disease (AD). For APOE e3/4 patients who develop AD, those with long poly-T repeats linked to APOE e3 developed AD on average 7 years earlier than those with shorter poly-T polymorphisms linked to APOE e3. We have replicated this finding in a distinct population. In APOE e3/e3 homozygotes there is also a significant correlation between the length of the poly-T variant and grey matter density, which is independent of APOE e4. TOMM40 is in linkage disequilibrium with APOE and encodes the protein Translocase of the Outer Mitochondrial Membrane. Our central hypothesis is that the poly-T tract controls expression of TOMM40 and APOE in brain, and thus regulates the pathways in which these proteins participate. We will test this hypothesis at the genomic, genetic and biochemical levels. We will precisely identify the long, short and the ancestral poly-T tracts, and correlate the age o onset of AD and AD risk to these alleles. We will test our working model that the poly-T tract regulates TOMM40 and APOE expression by measuring APOE and TOMM40 mRNA and protein levels in rapidly autopsied human brain samples, and correlate these changes with susceptibility to AD-related damage across different brain regions. We will also construct two humanized mouse models of the TOMM40-APOE linkage disequilibrium region, that will permit more detailed, mechanism-based studies of the regulation of expression of these genes. We will exchange the mouse TOMM4-APOE linkage disequilibrium region with the homologous human region. Both models will be made homozygous for human APOE e3, thus eliminating possible confounding effects of APOE e4, and we will make one homozygous for the short poly-T polymorphism while we will make the other homozygous for the long poly-T variant. Successfully fulfilling these aims will advance our understanding of the molecular mechanisms underlying the genetic risk factors in AD and will provide valuable pathways for developing an effective preventive therapy for late-onset Alzheimer's disease.