Immune Mechanisms Underlying the Neuroprotective Effects of Physical Activity in Human and Mouse Models of Genetic Risk for Alzheimers Disease

摘要 APOE β 4等位基因是晚发性阿尔茨海默病（AD）最重要的遗传危险因素。载脂蛋白E β 4 可能通过改变炎症、脂质稳态和/或淀粉样蛋白清除而导致AD风险。最近 遗传学研究表明，迟发性AD的先天免疫中存在多种途径，包括触发 髓样细胞受体2（TREM 2）基因。运动和体力活动（PA） 在外周和神经源性、血管生成性和抗炎性大脑中产生抗炎性变化 动物的变化。载脂蛋白E、先天免疫和AD之间的机制关系， 但是，要想发挥人民军的缓和作用，还有待建立。我们发表的关于认知完整的健康老年人的数据 18个月的随访结果表明，久坐的β 4携带者表现出明显较低的fMRI激活， 情节记忆表现较差，海马体积较小，白色物质扩散异常 与从事常规PA的104名运营商相比。最重要的是，这些群体差异并不是 在低PA和高PA非携带者之间观察到，这表明PA的神经保护作用是 特别是对AD遗传风险人群有效。其他初步研究表明，TREM 2 + 先天性免疫细胞在调节AD动物模型和潜在的AD病理中起直接作用， 在人类AD患者中。对于拟议的跨学科项目，我们的总体假设是PA 抵消了TREM 4等位基因的负面炎症效应，影响TREM 2和其他先天免疫 参与AD的途径，从而降低AD 4携带者的认知能力下降和AD的风险。这个项目 有两个具体目标。目标1将招募150名认知功能完整的健康老年人（年龄65-80岁）：75 APOE ≥ 4 携带者（103/104）和75/104非携带者（103/103）。参与者将接受最先进的PA测量 和健身;结构和功能3 T MRI;淀粉样蛋白PET成像;与AD相关的CSF/血液生物标志物， 炎症和运动;以及两次全面的记忆/认知测试，间隔24- 个月目标2类似于人类项目，将确定自愿车轮运行PA的影响 在AD的新型转基因小鼠模型中， 与APPPS 1（APPPS 1; APOE 3/3和APPPS 1; APOE 4/4）及对照菌株杂交。关键指标 包括：TREM 2+细胞、促炎标志物表达、脑Aβ42和空间记忆能力。 总之，这些互补的人类和动物研究将提供对潜在机制的关键见解 将APOE基因型、运动、炎症、AD脑病理和认知联系起来， 有针对性的治疗。

Abstract The APOE ϵ4 allele is the most important genetic risk factor for late onset Alzheimer's disease (AD). APOE ϵ4 may contribute to AD risk by altering inflammation, lipid homeostasis and/or amyloid clearance. Recent genetics studies have implicated multiple pathways in innate immunity in late-onset AD, including the triggering receptor expressed on the myeloid cells 2 (TREM2) gene. In contrast, exercise and physical activity (PA) produce anti-inflammatory changes in the periphery and neurogenic, angiogenic, and anti-inflammatory brain changes in animals. The mechanistic relationships between APOE, innate immunity, and AD, and the potential moderating influence of PA, remain to be established. Our published data on cognitively intact, healthy elders followed for 18 months indicate that sedentary ϵ4 carriers demonstrate significantly lower fMRI activation, poorer episodic memory performance, smaller hippocampal volumes, and abnormal white matter diffusion compared to ϵ4 carriers who engage in regular PA. Most importantly, these group differences were not observed between low and high PA non-carriers, suggesting that the neuroprotective effects of PA are especially potent for persons at genetic risk for AD. Additional preliminary studies demonstrate that TREM2+ innate immune cells play a direct role in regulating AD pathologies in both animal models of AD and potentially in human AD patients. For the proposed interdisciplinary project, our overall hypothesis posits that PA counteracts the negative inflammatory effects of the ϵ4 allele, affecting TREM2 and other innate immune pathways implicated in AD, thereby reducing the risk of cognitive decline and AD in ϵ4 carriers. This project has two specific aims. Aim 1 will recruit 150 cognitively intact, healthy elders (ages 65-80): 75 APOE ϵ4 carriers (ϵ3/ϵ4) and 75 ϵ4 non-carriers (ϵ3/ϵ3). Participants will undergo state-of-the-art measurements of PA and fitness; structural and functional 3T MRI; amyloid PET imaging; CSF/blood biomarkers related to AD, inflammation, and exercise; and comprehensive memory/cognition testing on two occasions separated by 24- months. Aim 2 is analogous to the human project and will determine the impact of voluntary wheel running PA across age (3 months, 6 months, and 9 months) in novel transgenic mouse models of AD humanized for ϵ3 and ϵ4 and crossed with APPPS1 (APPPS1; APOE3/3 and APPPS1; APOE4/4) and control strains. Key indices include: TREM2+ cells, expression of proinflammatory markers, brain Aβ42, and spatial memory performance. Together, these complementary human and animal studies will provide key insights into potential mechanisms linking APOE genotype, exercise, inflammation, AD brain pathology, and cognition that could ultimately be targeted therapeutically.