Genetic interaction of PICALM and APOE in Alzheimer's disease

PICALM 和 APOE 在阿尔茨海默病中的遗传相互作用

• 批准号: 9914200
• 负责人: Zhen Zhao
• 金额: $ 16.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914200
• 关键词: ATP binding cassette transporter 1; Abeta clearance; Abeta synthesis; Affect; Age-Years; Alleles; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amino Acids; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Apolipoproteins; Autophagocytosis; Binding; Biological; Blood - brain barrier anatomy; Brain; Cell Surface Proteins; Cells; Cholesterol; Clathrin; Clathrin Adaptors; Clathrin-Coated Vesicles; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Complex; Dementia; E protein; Elderly; Engineering; Etiology; Event; Exhibits; Foundations; Frequencies; Future; Genes; Genetic; Genetic Diseases; Genetic Polymorphism; Genotype; Goals; Health; Household; Human; Image; Impaired cognition; Impairment; In Vitro; Inherited; Late Onset Alzheimer Disease; Link; Lipids; Lysine; Maps; Mediating; Membrane; Metabolism; Modeling; Molecular; Molecular Probes; Mus; Mutation; Nerve Degeneration; Neurons; Outcome Study; Pathogenesis; Pericytes; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Play; Population Study; Positioning Attribute; Presenile Alzheimer Dementia; Protein Isoforms; Regulation; Reporting; Risk; Senile Plaques; Short-Term Memory; Surface; Testing; Therapeutic; abeta toxicity; age related; apolipoprotein E-4; base; beta secretase; blood-brain barrier permeabilization; cognitive testing; cohort; epsin; exosome; gamma secretase; genetic risk factor; genome sequencing; genome wide association study; genomic locus; in vivo; insight; mouse model; neurodegenerative phenotype; neurofibrillary tangle formation; presenilin-1; presenilin-2; protein function; receptor; receptor internalization; relating to nervous system; risk variant; synergism; tau Proteins; therapeutic target; trafficking

SUMMARY Alzheimer's disease (AD) is the most common form of dementia in the elderly, manifesting progressive neurodegenerative conditions including amyloid plaque and neurofibrillary tangle formation, and cognitive impairment. Genetic inheritance is estimated to determine nearly 80% of the AD cases. Besides the well-known familial mutations in APP, PSEN1 and PSEN2 genes found in early-onset AD cases, over 30 loci or genes are associated sporadic late-onset AD (LOAD) as indicated by recent genome-wide association studies and whole exosome/genome sequencing projects. APOE and PICALM are among the top of the list. APOE encodes the lipid carrier apolipoprotein E protein. Among its three major isoforms (ε2, ε3, and ε4), ε3 is the most common isoform, ε4 is unarguably the strongest genetic risk factor for LOAD, and ε2 is the less frequent but is protective for AD. These isoforms also differentially affect molecular and cellular events that are important for amyloid β (Aβ) metabolism and neurodegeneration. On the other hand, PICALM encodes the phosphatidylinositol binding clathrin assembly protein, and is confirmed by nearly all GWAS studies as a major AD-associated gene. PICALM controls receptor internalization and subsequent intracellular trafficking of clathrin-coated vesicles. It plays key roles in mediating brain clearance of Aβ, regulating activities of β- and γ-secretases for Aβ production, mitigating Aβ toxicity in neurons, and promoting Tau clerance via autophagy. More interestingly, the unique genetic interaction between APOE and PICALM in AD has been demonstrated based on population studies, as PICALM genotypes at multiple AD-associated confer risk predominantly in ε4 carriers, and AD risk PICALM rs3851179G allele and APOE ε4 allele synergistically affect cortex volume and working memory function in AD patients. However, the mechanism underpinning this interaction in AD is still unknown. Based on the PICALM's interactome and functions in maintaining cell surface protein functions, as well as our preliminary findings showing impaired APOE lipidation and reduced level of surface ABCA1 cholesterol and phospholipid transporter in PICALM deficient mice, we hypothesize that PICALM may facilitate APOE lipidation and Aβ metabolism by controlling the function of ABCA1 transporter, and therefore risk PICALM rs3851179G and APOE ε4 alleles adversely affect AD pathogenesis. To test this hypothesis, we propose to: i) determine the cellular and molecular mechanisms of PICALM in facilitating APOE lipidation and characterize PICALM- dependent internalization and trafficking of ABCA1 transporter (AIM 1); ii) explore the functional impact of PICALM and APOE's synergistic interaction in vivo on neurodegenerative phenotypes (AIM 2). We expect to gather first-hand evidence that the risk alleles of two genes synergistic influence AD pathogenesis, and establish the molecular and cellular mechanisms of interaction between APOE and PICALM both in vitro and in vivo. The outcomes of the studies will provide new insights into the inheritability, etiology and pathogenesis of AD, and serve as a foundation for future studies to therapeutically target this interaction for AD diagnosis and treatment.

总结 阿尔茨海默病（AD）是老年人中最常见的痴呆形式，表现为进行性痴呆， 神经退行性疾病，包括淀粉样蛋白斑和神经纤维缠结形成，以及认知障碍。 损伤据估计，基因遗传决定了近80%的AD病例。除了众所周知的 在早发性AD病例中发现的APP、PSEN 1和PSEN 2基因的家族性突变中，超过30个位点或基因被 最近的全基因组关联研究表明， 外泌体/基因组测序项目。APOE和PICALM是其中的佼佼者。APOE编码 脂质载体载脂蛋白E蛋白。在其三种主要亚型（ε2、ε3和ε4）中，ε3是最常见的 ε4是LOAD最强的遗传风险因子，ε2是频率较低但具有保护性的因子 对于AD。这些异构体也不同地影响对淀粉样蛋白β重要的分子和细胞事件 （Aβ）代谢和神经变性。另一方面，PICALM编码磷脂酰肌醇结合 网格蛋白组装蛋白，并确认了几乎所有的GWAS研究作为一个主要的AD相关基因。PICALM 控制受体内化和随后的网格蛋白包被囊泡的细胞内运输。它起着关键作用 在介导Aβ的脑清除、调节Aβ产生的β-和γ-分泌酶活性、减轻 神经元中的Aβ毒性，并通过自噬促进Tau清除。更有趣的是， 在AD中APOE和PICALM之间的相互作用已经基于人群研究得到证实，如PICALM 多个AD相关基因型主要在ε4携带者中赋予风险，并且AD风险PICALM rs3851179 G 等位基因和APOE ε4等位基因协同影响AD患者的大脑皮层体积和工作记忆功能。 然而，这种相互作用在AD中的机制仍然是未知的。 基于PICALM的相互作用组和维持细胞表面蛋白功能的功能，以及我们的 初步结果显示APOE脂化受损和表面ABCA 1胆固醇水平降低， PICALM缺陷小鼠的磷脂转运蛋白，我们推测PICALM可能促进APOE脂化 和Aβ代谢通过控制ABCA 1转运蛋白的功能，因此风险PICALM rs3851179 G和 APOE ε4等位基因对AD发病机制有不利影响。为了验证这一假设，我们建议：i）确定 PICALM促进APOE脂化的细胞和分子机制，并表征PICALM- ABCA 1转运蛋白（AIM 1）的依赖性内化和运输; ii）探索 PICALM和APOE在体内对神经退行性表型（AIM 2）的协同作用。我们期望 收集第一手证据，证明两个基因的风险等位基因协同影响AD发病机制，并建立 APOE和PICALM在体外和体内相互作用的分子和细胞机制。的 这些研究的结果将为AD的遗传性、病因学和发病机制提供新的见解， 作为未来研究的基础，以治疗为目标，这种相互作用的AD诊断和治疗。