Brain cPLA2 as a mechanism for neuroinflammation in AD/ADRD with and without APOE4

大脑 cPLA2 作为 AD/ADRD 神经炎症的机制，有或没有 APOE4

• 批准号: 10464564
• 负责人: Zoe Arvanitakis
• 金额: $ 241.77万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464564
• 关键词: Address; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Attenuated; Autopsy; Blood Vessels; Brain; Brain Infarction; Calcium; Cells; Cessation of life; Clinical; Cognitive; Cohort Studies; Data; Dementia; Development; Encephalitis; Endothelial Cells; Enzymes; Freezing; Gene Expression; Genotype; Goals; Human; Impaired cognition; Individual; Infarction; Inflammation; Inflammatory Response; Late Onset Alzheimer Disease; Learning; MAPK8 gene; Measures; Mediating; Memory; Mitogen-Activated Protein Kinase Inhibitor; Molecular; Mus; Nerve Degeneration; Neuroglia; Neurologist; Neurons; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Phospholipase A2; Phosphorylation; Protein Isoforms; Proteins; Public Health; Recombinants; Risk; Risk Factors; Role; Sampling; Senile Plaques; Signal Pathway; Signal Transduction; Subgroup; Synaptosomes; Testing; Therapeutic; Tissues; Validation; Vascular Diseases; advanced dementia; animal data; apolipoprotein E-4; brain cell; brain tissue; cell type; cognitive function; dementia risk; design; druggable target; frontal lobe; genetic risk factor; improved; improved outcome; inflammatory marker; inhibitor; insight; interest; lipid metabolism; mild cognitive impairment; mouse model; neuroinflammation; neuropathology; novel; religious order study; secondary analysis

Abstract The elucidation of potentially modifiable molecular pathways involved in Alzheimer’s disease (AD)/Alzheimer’s Disease Related Dementia (ADRD) is of great scientific interest and offers hope for improved public health. Mounting evidence points to the role of calcium-dependent phospholipase A2 (cPLA2) in ADRD. Indeed, cPLA2 expression is increased around amyloid plaques in patients with AD and is associated with a brain inflammatory response. And, reducing cPLA2 gene expression improves learning and memory in AD mouse models. Further, APOE4, the strongest genetic risk factor for late-onset AD, has been shown to promote and accelerate brain inflammation, while the underlying mechanisms are not well understood. The overall goal of this project is to test the hypothesis that cPLA2 activation is associated with faster cognitive decline in APOE4 carriers by accelerating brain inflammation and AD and vascular pathology. Leveraging brain biospecimens and detailed clinical and neuropathological data from the Religious Order Study (ROS) cohort, we propose the following three Aims. In Aim 1, we will examine the patterns of cPLA2 activation and signaling pathways in older subjects across a range of cognitive function, stratified by APOE4 using frozen human brain samples and single brain cell types isolated from a subset of samples. In Aim 2, we will use ex vivo stimulation to study cPLA2 activation and signaling mechanisms in neurons and glia of post-mortem brain tissues, stratified by APOE4 and cognitive function. In Aim 3, we will investigate whether the association between the prodromal decline in global cognitive and APOE genotype is mediated by cPLA2 activation. In addition, we will explore if inflammation, AD neuropathological markers (Aβ, pTau, or both) and other vascular pathological markers mediate this association. This project will elucidate a novel mechanism for APOE4 induced brain inflammation in AD/ADRD. The study of available brain tissues from well-characterized autopsied persons with a range of clinical and pathologic phenotypes will provide deep insights into cell specific cPLA2 activation profiles in relation to APOE4 and markers of inflammation. Identifying a role for cPLA2 activation in AD inflammation is a significant step toward the development of cPLA2 inhibitors, and ultimately improved treatments for AD/ADRD.

摘要 阿尔茨海默病中潜在可修饰分子通路的阐明 (AD)/阿尔茨海默病相关痴呆症(ADRD)具有极大的科学价值，并带来了希望 以改善公众健康。越来越多的证据表明钙依赖的作用 ADRD中磷脂酶A2(CPLA2)的表达。事实上，cPLA2在淀粉样蛋白周围的表达增加。 阿尔茨海默病患者中的斑块与脑部炎症反应有关。以及，减少 CPLA2基因表达可改善AD模型小鼠的学习记忆能力。此外，APOE4， 迟发性阿尔茨海默病的最强遗传风险因素，已被证明促进和加速 脑部炎症，但其潜在机制尚不清楚。的总目标是 这个项目是为了验证cplA2激活与认知速度加快相关的假设。 APOE4携带者通过加速脑部炎症和AD和血管病理而下降。 利用脑生物样品以及来自 宗教秩序研究(ROS)队列，我们提出以下三个目标。在目标1中，我们将 研究一系列老年受试者中cPLA2激活和信号通路的模式 APOE4使用冷冻的人脑样本和单个脑细胞对认知功能进行分层 从样本子集中隔离的类型。在目标2中，我们将使用体外刺激来研究cPLA2 死后脑组织神经元和神经胶质细胞的激活和信号机制 受载脂蛋白4和认知功能的影响。在目标3中，我们将调查两者之间的关联 全球认知型和载脂蛋白E基因的先兆下降是由cPLA2激活介导的。 此外，我们将探索炎症、AD神经病理标志物(Aβ、PTAU或两者)和 其他血管病理标记物介导这种联系。这个项目将阐明一部小说 APOE4诱导AD/ADRD大鼠脑炎症的机制关于有效脑的研究 来自具有不同临床和病理特征的尸检人员的组织 表型将提供对与以下相关的细胞特异性cPLA2激活谱的深入了解 载脂蛋白E4和炎症标志物。确定cPLA2激活在AD炎症中的作用 是朝着开发cPLA2抑制剂迈出的重要一步，并最终得到改善 AD/ADRD的治疗。