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.

概括 阿尔茨海默氏病（AD）是老年痴呆的最常见形式 神经退行性疾病，包括淀粉样斑块和神经原纤维缠结以及认知 损害。估计遗传遗传可以确定几乎80％的AD病例。除了众所周知 在早期发作AD病例中发现的APP，PSEN1和PSEN2基因的家族突变，超过30个基因座或基因是 如最近的全基因组关联研究和整体所示，相关的零星后期AD（负载）（负载） 外部/基因组测序项目。 APOE和PICALM是列表的顶端。 Apoe编码 脂质载体载脂蛋白E蛋白。在其三个主要同工型（ε2，ε3和ε4）中，ε3是最常见的 同工型，ε4毫无疑问是负载强的遗传风险因素，而ε2是较少的频率，但受到保护 对于广告。这些同工型也不同地影响分子和细胞事件，这对于淀粉样蛋白β很重要 （Aβ）代谢和神经退行性。另一方面，PICALM编码磷脂酰肌醇结合 网格蛋白组装蛋白，几乎所有GWAS研究都证实了与广告相关的主要基因。皮基 控制受体内在化以及随后的细胞内涂层蔬菜的细胞内运输。它扮演钥匙 在介导Aβ的大脑清除率，调节β-和γ-分泌酶的活性中的作用，以减轻Aβ的产生 Aβ在神经元中的毒性，并通过自噬来促进tau神经。更有趣的是，独特的遗传 根据人群研究，已经证明了APOE和PICAL之间的APOE和PICALM之间的相互作用，因为PICALM 在ε4载体中主要是多个AD相关会议风险的基因型，并且AD风险Picalm rs3851179g 等位基因和APOEε4等位基因在AD患者中协同影响皮层体积和工作记忆功能。 但是，在AD中进行这种相互作用的基础的机制尚不清楚。 基于皮卡的相互作用组和维持细胞表面蛋白功能的功能，以及我们 初步发现显示APOE脂化受损，表面ABCA1胆固醇水平降低， 磷脂转运蛋白缺乏小鼠，我们假设皮基可能促进apoE脂质 和Aβ代谢通过控制ABCA1转运蛋白的功能，因此风险是Picalm rs3851179g和 APOEε4等位基因不利影响AD发病机理。为了检验这一假设，我们建议：i）确定 皮层的细胞和分子机制在促进apoe脂质方面的表征 ABCA1转运蛋白的依赖性内在化和贩运（AIM 1）； ii）探索功能影响 PICALM和APOE在神经退行性表型上体内的协同相互作用（AIM 2）。我们希望 收集第一手证据表明，两个基因的风险等位基因协同影响AD发病机理，并建立 ApoE和Picalm之间相互作用的分子和细胞机制在体外和体内。这 研究结果将为AD的遗传性，病因和发病机理提供新的见解，以及 作为未来研究的基础，以治疗将这种相互作用定位为AD诊断和治疗。