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.

抽象的 阐明参与阿尔茨海默氏病的潜在可修改分子途径 （AD）/阿尔茨海默氏病有关的痴呆症（ADRD）具有极大的科学兴趣，并提供了希望 为了改善公共卫生。安装证据指向钙依赖性的作用 ADRD中的磷脂酶A2（CPLA2）。实际上，淀粉样蛋白周围的CPLA2表达增加 AD患者的斑块，与脑炎症反应有关。而且，还原 CPLA2基因表达可改善AD鼠标模型中的学习和记忆。此外，apoe4， 已显示出强大的遗传危险因素已被证明可以促进和加速 大脑感染，而潜在的机制尚不清楚。总体目标 该项目是为了测试CPLA2激活与更快的认知有关的假设 通过加速脑感染和AD和血管病理，APOE4载体的下降。 利用大脑生物测量以及详细的临床和神经病理学数据 宗教秩序研究（ROS）队列，我们​​提出以下三个目标。在AIM 1中，我们将 检查范围内老年受试者中CPLA2激活和信号通路的模式 认知功能，使用冷冻的人脑样品和单脑细胞通过APOE4分层 从样品子集隔离的类型。在AIM 2中，我们将使用离体刺激来研究CPLA2 尸体后脑组织的神经元和神经胶质的激活和信号传导机制，分层 由APOE4和认知功能。在AIM 3中，我们将调查是否 CPLA2激活介导了全球认知和APOE基因型的前序下降。 此外，我们将探讨感染，AD神经病理学标记（Aβ，PTAU或两者）和 其他血管病理标记介导了这种关联。这个项目将阐明一本小说 APOE4的机制在AD/ADRD中诱导脑注射。可用大脑的研究 具有一系列临床和病理范围的尸体锻炼人的组织 表型将提供有关细胞特异性CPLA2激活曲线的深入见解 APOE4和炎症标记。确定CPLA2激活在AD炎症中的作用 是迈向开发CPLA2抑制剂的重要一步，并最终改善 AD/ADRD的治疗。