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.

外周与脑髓样免疫史在衰老和阿尔茨海默氏症认知下降中的作用 疾病 衰老的特征是有害免疫回报的发展，持续的促炎症 反应会促进最终器官损害，包括脆弱，血管疾病，代谢综合征和癌症。 大脑也很容易受到衰老的影响，这是认知能力下降和 阿尔茨海默氏病（AD）。人类全基因组中髓样丧失功能变体的优势 联想研究（GWAS）导致着眼于了解脑小胶质细胞在衰老和AD中的作用。 但是，大多数髓样细胞存在于大脑之外，以及周围髓样的作用 尚未正式测试与年龄和广告相关认知下降的发展中的隔室。在 该应用程序，我们将使用新颖的方法来测试周围髓样系统的作用，并将其对比 小胶质细胞在与衰老和积累相关的认知下降中的作用中 淀粉样蛋白的老化和AD的临床前鼠模型。我们将测试与年龄相关的变化 仅外周髓样系统就足以促进认知能力下降，相反，是否小胶质 仅功能障碍就会导致认知能力下降，而与周围髓样系统无关。分开 来自脑髓样系统的周围，我们将使用一种新型的骨髓移植方法和一个 完全靶向小胶质细胞的遗传策略比较每个髓样的相对贡献 与年龄相关的认知下降和认知下降与积累相关的认知下降和认知下降 炎性淀粉样蛋白肽。使用Trem1（触发受体在髓样细胞1上表达） 作为代表，髓样特异性途径在两个隔间中表达的途径，我们将解析 外周髓样细胞与脑小胶质细胞对年龄和广告相关的认知的相对贡献 在目标1和2中，衰落和定义了这些贡献基础的作用的免疫代谢机制。 AIM 3，我们将确定人类髓样细胞中TREM1介导的免疫血液的功能。 了解大脑小胶质细胞与外周髓样室对年龄和年龄的相对贡献 与广告相关的认知能力下降将为有效的，改善疾病的疗法的发展提供信息。