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 阐明与阿尔茨海默氏病有关的潜在可修饰分子途径 (AD)/阿尔茨海默病相关痴呆 (ADRD) 具有重大科学意义并带来希望 以改善公共卫生。越来越多的证据表明钙依赖性的作用 ADRD 中的磷脂酶 A2 (cPLA2)。事实上，淀粉样蛋白周围的 cPLA2 表达增加 AD 患者的斑块与大脑炎症反应有关。并且，减少 cPLA2 基因表达可改善 AD 小鼠模型的学习和记忆能力。进一步地，APOE4， 晚发性 AD 的最强遗传风险因素，已被证明可以促进和加速 大脑炎症，而其潜在机制尚不清楚。总体目标为 该项目旨在测试 cPLA2 激活与更快的认知能力相关的假设 通过加速脑部炎症、AD 和血管病理学，APOE4 携带者数量下降。 利用大脑生物样本和详细的临床和神经病理学数据 针对宗教秩序研究（ROS）群体，我们提出以下三个目标。在目标 1 中，我们将 检查一系列老年受试者的 cPLA2 激活模式和信号通路 使用冷冻人脑样本和单个脑细胞通过 APOE4 进行分层的认知功能 从样本子集中分离出的类型。在目标 2 中，我们将使用离体刺激来研究 cPLA2 死后脑组织神经元和神经胶质细胞的激活和信号传导机制，分层 APOE4 和认知功能。在目标 3 中，我们将研究两者之间是否存在关联 整体认知和 APOE 基因型的前驱下降是由 cPLA2 激活介导的。 此外，我们将探讨炎症、AD 神经病理学标志物（Aβ、pTau 或两者）是否和 其他血管病理标志物介导这种关联。该项目将阐明一部小说 APOE4 诱导 AD/ADRD 脑炎症的机制。可用大脑的研究 来自具有一系列临床和病理特征的尸检者的组织 表型将提供对细胞特异性 cPLA2 激活谱的深入了解 APOE4 和炎症标志物。确定 cPLA2 激活在 AD 炎症中的作用 是 cPLA2 抑制剂开发的重要一步，并最终得到改善 AD/ADRD 的治疗。