Resolving the genetic interaction between DAB1 and APOE4 in Alzheimer's.

APOE-ε4（APOE 4）变异是发展迟发性阿尔茨海默病（AD）的最大单一风险因素;然而，其在AD中的参与知之甚少。最近，在英国生物库中，DAB 1被确定为纯合子APOE 4（e4/e4）个体中唯一的全基因组显著位点。DAB 1与AD的关系与e4/e4基因型和DAB 1 SNP的接合性密切相关，而E4/e4基因型和DAB 1 SNP的接合性影响AD的发病概率和发病年龄。基于此，我们假设APOE 4和DAB 1之间存在遗传相互作用，协同增加AD的可能性。APOE 4和DAB 1均作用于APOE受体家族中的内吞信号受体，并对Aβ蓄积和微管结合蛋白τ（MAPT）磷酸化产生影响，表明可能存在功能重叠。DAB 1是REELIN信号通路上的一种专性衔接蛋白，其在脑发育中的作用已得到充分表征。Reln基因已被证明会影响该疾病小鼠模型中的AD相关表型，并且在APOE 4研究中，RELN与e4/e4个体中的AD名义上相关，这表明RELN-DAB 1途径在AD中的参与更广泛。我们建议确定Dab 1剂量依赖性，AD相关的表型，在小鼠和培养模型中被APOE 4夸大，将有助于阐明这些基因如何导致疾病风险增加。我们将通过追求以下具体目标来调查这一点：具体目标1。确定Dab 1杂合性是否以APOE变体依赖性方式改变早期和/或晚期AD样病理。具体目标2。确定Dab 1基因剂量是否影响APOE 4依赖性内吞畸变。我们的长期目标是解决DAB 1和其他REELIN通路基因如何影响APOE 4生物学，以了解这种载脂蛋白和内吞作用缺陷如何促进AD的进展。

The APOE-ε4 (APOE4) variant is the greatest single risk factor for developing late-onset Alzheimer's disease (AD); however, its involvement in AD is poorly understood. Recently DAB1 was identified as the only genome-wide significant locus in homozygous APOE4 (e4/e4) individuals in the UK Biobank. DAB1's involvement in AD was profoundly dependent on the e4/e4 genotype and also the DAB1 SNP zygosity, which influenced the probability of developing AD and the age of onset. Based on this, we hypothesize that there is a genetic interaction between APOE4 and DAB1 that synergistically augments the likelihood of AD. Both APOE4 and DAB1 act on the endocytosis-signaling receptors in the APOE-receptor family and have consequences for Aβ accumulation and microtubule binding protein τ (MAPT) phosphorylation pointing to potential functional overlap. DAB1 is an obligate adaptor protein on the REELIN signaling pathway that is well characterized for its roles in brain development. The Reln gene has been shown to impact AD-related phenotypes in mouse models of the disease, and in the APOE4 study RELN was nominally associated with AD in e4/e4 individuals pointing to a broader involvement of the RELN-DAB1 pathway in AD. We propose that determining the Dab1 dosage-dependent, AD-related phenotypes that are exaggerated by APOE4 in mouse and culture models will help elucidate how these genes contribute to the increased risk of the disease. We will investigate this by pursuing the following specific aims: Specific Aim 1. To determine if Dab1 heterozygosity alters early and/or late AD-like pathology in an APOE variant-dependent manner. Specific Aim 2. To determine if Dab1-gene dose influences APOE4-dependent endocytic aberrations. Our long term goal is to resolve how DAB1 and other REELIN pathway genes influence APOE4 biology as a means to understand how this apolipoprotein and defects in endocytosis contribute to the progression of AD.