The role of peripheral versus brain myeloid immunity in the cognitive decline of aging and Alzheimer's disease

外周与脑髓免疫在衰老和阿尔茨海默病认知能力下降中的作用

• 批准号: 10524957
• 负责人: Katrin I. Andreasson
• 金额: $ 174.94万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524957
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amplifiers; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Autopsy; Biological Models; Blood; Bone Marrow; Bone Marrow Transplantation; Brain; Clinical; Cognitive aging; Cognitive deficits; Data; Development; Disease; Energy Metabolism; Functional disorder; Genetic; Genetic Models; High Prevalence; Hippocampus (Brain); Human; Human Genome; Immune; Immune response; Immunity; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Lead; Malignant Neoplasms; Mediating; Memory Loss; Metabolic; Metabolic syndrome; Metabolism; Microglia; Modeling; Mus; Myelogenous; Myeloid Cells; Neurodegenerative Disorders; Organ; Pathology; Pathway interactions; Peripheral; Pre-Clinical Model; Research; Role; Severities; System; TREM2 gene; Testing; Tissues; Translating; Variant; Vascular Diseases; aging brain; cognitive development; effective therapy; experimental study; frailty; genetic approach; genetic variant; genome wide association study; human model; innate immune pathways; loss of function; macrophage; monocyte; mouse model; mutant; neurotoxic; neutrophil; novel; novel strategies; pre-clinical; prevent; receptor; response; transcriptomics

The role of peripheral versus brain myeloid immunity in cognitive decline of aging and Alzheimer’s disease Aging is characterized by the development of detrimental immune responses, where sustained pro-inflammatory responses promote end-organ damage, including frailty, vascular disease, metabolic syndrome, and cancer. The brain is also highly vulnerable to aging, as demonstrated by the high prevalence of cognitive decline and Alzheimer’s disease (AD). The preponderance of myeloid loss-of-function variants in human genome-wide association studies (GWAS) had led to a focus on understanding the role of brain microglia in aging and in AD. However, the majority of myeloid cells exist outside of the brain, and the role of the peripheral myeloid compartment in the development of age- and AD-associated cognitive decline has not been formally tested. In this application, we will use novel approaches to test the role of the peripheral myeloid system and contrast that with the role of microglia in the development of cognitive decline associated with aging and accumulation of amyloid in preclinical murine models of aging and AD. We will test whether age-associated changes in the peripheral myeloid system alone are sufficient to promote cognitive decline, and conversely, whether microglial dysfunction alone can cause cognitive decline, independent of the peripheral myeloid system. To separate out the peripheral from brain myeloid systems, we will use a novel bone marrow transplantation approach and a complementary genetic strategy targeting microglia to compare the relative contributions of each myeloid compartment to age-associated cognitive decline and cognitive decline associated with accumulation of inflammatory amyloid-ß peptides. Using the TREM1 (Triggering Receptor Expressed on Myeloid cells-1) pathway as a representative, myeloid-specific pathway expressed in both compartments, we will parse out the relative contributions of peripheral myeloid cells versus brain microglia to age- and AD-associated cognitive decline and define immune-metabolic mechanisms of action underlying these contributions in Aims 1 and 2. In Aim 3, we will determine the function of TREM1-mediated immune responses in human myeloid cells. Understanding the relative contributions of the brain microglial vs peripheral myeloid compartments to age- and AD-associated cognitive decline will inform development of effective, disease-modifying therapies.

外周免疫与脑髓免疫在衰老和阿尔茨海默病认知能力下降中的作用 疾病 衰老的特点是不健康的免疫反应的发展，其中持续的促炎症反应 反应会促进终末器官损伤，包括虚弱、血管疾病、代谢综合征和癌症。 大脑也极易受到衰老的影响，认知能力下降和衰老的高发率就证明了这一点。 阿尔茨海默病（AD）在人类全基因组中髓样功能丧失变异占主导地位。 关联研究 (GWAS) 引起人们对了解大脑小胶质细胞在衰老和 AD 中的作用的关注。 然而，大多数骨髓细胞存在于大脑之外，外周骨髓细胞的作用 与年龄和 AD 相关的认知衰退的发展过程尚未经过正式测试。 在这个应用中，我们将使用新的方法来测试外周骨髓系统的作用并对比 小胶质细胞在与衰老和积累相关的认知衰退的发展中的作用 我们将测试衰老和 AD 临床前小鼠模型中的淀粉样蛋白是否与年龄相关。 仅外周髓系统就足以促进认知能力下降，反之，小胶质细胞是否 单独的功能障碍可导致认知能力下降，与外周髓系统无关。 对于来自脑髓系统的外周血，我们将使用一种新颖的骨髓移植方法和 针对小胶质细胞的互补遗传策略，以比较每个骨髓细胞的相对贡献 与年龄相关的认知能力下降和与积累相关的认知能力下降 使用 TREM1（骨髓细胞上表达的触发受体 -1）的炎症性淀粉样蛋白 -β 肽。 通路作为在两个区室中表达的代表性骨髓特异性通路，我们将解析出 外周骨髓细胞与脑小胶质细胞对年龄和 AD 相关认知的相对贡献 减少并定义目标 1 和 2 中这些贡献背后的免疫代谢作用机制。 目标 3，我们将确定 TREM1 介导的人类骨髓细胞免疫反应的功能。 了解大脑小胶质细胞与外周髓细胞室对年龄和年龄的相对贡献 AD 相关的认知能力下降将为开发有效的疾病缓解疗法提供信息。