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

解决阿尔茨海默病中 DAB1 和 APOE4 之间的遗传相互作用。

• 批准号: 10591034
• 负责人: Brian W. Howell
• 金额: $ 24.45万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591034
• 关键词: Abeta synthesis; Adaptor Signaling Protein; Adult; Age of Onset; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoproteins; Area; Binding; Binding Proteins; Biology; Brain; Cell Surface Receptors; Cell membrane; Cell physiology; Cell surface; Collaborations; Cytoplasmic Tail; Defect; Development; Disease; Disease Progression; Disease model; Dose; Endocytosis; Endosomes; Family; Functional disorder; Generations; Genes; Genetic; Genetic Epistasis; Genetic Risk; Genetic Transcription; Genotype; Goals; Heterozygote; Histologic; Human; Individual; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Lipids; Microtubules; Modeling; Mus; Neurons; Pathology; Pathway interactions; Phenotype; Phosphorylation; Population; Positioning Attribute; Price; Probability; Receptor Inhibition; Receptor Signaling; Reelin Signaling Pathway; Risk; Risk Factors; Role; Senile Plaques; Signal Transduction; Testing; Tyrosine Phosphorylation; Variant; abeta accumulation; antagonist; apolipoprotein E-3; apolipoprotein E-4; biobank; disorder risk; dosage; genome wide association study; genome-wide; mouse model; receptor; receptor internalization; reelin receptor; tau Proteins

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.

载脂蛋白E-ε4(apoE-apoe4)变异是发生晚发性阿尔茨海默病(AD)的最大单一危险因素；然而，它与AD的关系尚不清楚。最近，DAB1被确定为英国生物库中APOE4(e4/e4)纯合子个体中唯一的全基因组显著基因座。DAB1的S参与AD的发生与其e4/e4基因和DAB1SNP合子密切相关，进而影响AD的发生概率和发病年龄。在此基础上，我们假设APOE4和DAB1之间存在基因相互作用，协同增加AD的可能性。APOE4和DAB1都作用于APOE受体家族中的内吞信号受体，并导致Aβ的积累和微管结合蛋白τ的磷酸化，表明存在潜在的功能重叠。DAB1是Reelin信号通路上的专有接头蛋白，因其在大脑发育中的作用而被很好地描述。Reln基因已被证明影响AD相关表型在疾病的小鼠模型中，在APOE4研究中，RELN名义上与e4/e4个体中的AD相关，表明RELN-DAB1途径在AD中有更广泛的参与。我们认为，在小鼠和培养模型中确定APOE4夸大的Dab1剂量依赖的AD相关表型将有助于阐明这些基因是如何导致疾病风险增加的。我们将通过追求以下特定目标来研究这一点：特定目标1.确定Dab1杂合性是否以APOE变体依赖的方式改变早期和/或晚期AD样病理。具体目的2.确定Dab1基因剂量是否影响APOE4依赖的内吞畸变率。我们的长期目标是解决DAB1和其他Reelin途径基因如何影响APOE4生物学，以此作为了解载脂蛋白和内吞缺陷如何促进AD进展的一种手段。