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

外周与脑髓系免疫在老年认知功能减退和阿尔茨海默病中的作用 疾病 衰老的特征是有害免疫反应的发展，其中持续的促炎性反应是免疫系统的一个重要组成部分。 反应促进终末器官损伤，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，正如认知能力下降的高患病率所证明的那样， 阿尔茨海默病（AD）。人类全基因组髓系功能丧失变异的优势 相关研究（GWAS）的研究已经导致了对脑小胶质细胞在衰老和AD中的作用的关注。 然而，大多数髓细胞存在于脑外，外周髓细胞的作用 在年龄和AD相关的认知能力下降的发展中的作用尚未得到正式的测试。在 在本申请中，我们将使用新的方法来测试外周骨髓系统的作用，并对比 与小胶质细胞在与衰老和积累相关的认知能力下降的发展中的作用有关， 在衰老和AD的临床前鼠模型中的淀粉样蛋白。我们将测试是否与年龄相关的变化， 外周骨髓系统本身就足以促进认知能力的下降，反之，无论是小胶质细胞 功能障碍单独会导致认知能力下降，与外周骨髓系统无关。以分离出 从脑骨髓系统的外周，我们将使用一种新的骨髓移植方法和 互补遗传策略靶向小胶质细胞，以比较每种髓样细胞的相对贡献 与年龄相关的认知衰退和与累积 炎性淀粉样蛋白-β-肽。使用TREM 1（髓样细胞上表达的触发受体-1） 通路作为一个代表性的，骨髓特异性的通路在两个区室中表达，我们将解析出 外周骨髓细胞与脑小胶质细胞对年龄和AD相关认知功能的相对贡献 下降并定义目标1和2中这些贡献背后的免疫代谢作用机制。在 目的3，我们将确定TREM 1介导的免疫应答在人骨髓细胞中的功能。 了解脑小胶质细胞与外周髓样隔室对年龄的相对贡献， AD相关的认知功能下降将为开发有效的疾病改善疗法提供信息。

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.