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的可改变的分子通路的阐明 (AD)阿尔茨海默病相关痴呆症（ADRD）具有很大的科学意义，并提供了希望 来改善公众健康。越来越多的证据表明钙依赖性 磷脂酶A2（cPLA 2）。事实上，淀粉样蛋白周围cPLA 2表达增加， 斑块，并与脑炎症反应有关。而且， cPLA 2基因表达改善AD小鼠模型的学习和记忆。此外，APOE 4， 迟发性AD最强的遗传风险因素，已被证明可以促进和加速 脑炎症，而其潜在机制还不清楚。的总目标 该项目旨在验证cPLA 2激活与更快的认知能力相关的假设。 通过加速脑炎症和AD以及血管病理学来减少APOE 4携带者。 利用脑生物标本和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的。在目标1中，我们 研究cPLA 2激活和信号通路的模式，在老年受试者在一个范围内， 认知功能，使用冷冻人脑样本和单个脑细胞按APOE 4分层 从样本子集中分离的类型。在目标2中，我们将使用离体刺激来研究cPLA 2 死后分层脑组织神经元和神经胶质的激活和信号机制 APOE 4和认知功能。在目标3中，我们将研究 总体认知和APOE基因型的前驱期下降由cPLA 2激活介导。 此外，我们将探讨炎症、AD神经病理学标志物（Aβ、pTau或两者）和 其它血管病理学标记介导这种关联。这个项目将阐释一部小说 APOE 4诱导AD/ADRD脑炎症的机制。可用脑的研究 来自具有一系列临床和病理特征的良好尸检人员的组织 表型将提供深入了解细胞特异性cPLA 2激活概况， APOE 4和炎症标志物。确定cPLA 2激活在AD炎症中的作用 是cPLA 2抑制剂开发的重要一步，并最终改善 治疗AD/ADRD。