The relationship of AD risk factors to reactive astrogliosis along the Alzheimer's disease continuum

项目2概要/摘要 健康风险因素，如心血管风险因素（CVRF）和睡眠不足被认为会增加风险 老年痴呆症（AD）尽管CVRF和睡眠不良与AD病理学之间的联系机制仍然存在， 神经炎症，如星形胶质细胞增生，可能就是这样一种途径。 CVRF与AD病理学有着一致的联系：在过去10年的项目中，我们探索了 Aβ沉积单独和与血管调节剂联合与神经元功能障碍的关系，以及 与认知障碍和AD进展的关系。我们发现， Aβ负荷增加时的动脉僵硬度、收缩压和胆固醇稳态 除了CVRF，睡眠也是AD的一个危险因素。睡眠与大脑有着明确的联系 结构和途径参与AD，并对认知，免疫和其他生理功能至关重要。 功能协调发展的年龄和疾病相关的睡眠变化可能会影响AD病理学的积累21，22。 睡眠丧失与间质间隙中Aβ水平升高相关，并影响Aβ和A β的动力学。 脑脊液中的tau蛋白我们和其他人已经证明，睡眠质量差，客观性低， 睡眠效率（见初步数据）与更大Aβ负荷相关。此外，通过这一方案， 在一项研究中，我们发现Aβ与睡眠效率较差的人的遗忘之间存在更强的关联。 总之，这些数据表明，CVRF和睡眠不足可能会导致AD病理的脆弱性。 尽管如此，这些健康因素导致AD易感性增加的机制 仍然不清楚。一个潜在的介导因素是神经炎症。细胞炎症起到了很好的作用- 在AD病理学中的作用。炎症与CVRF、高血压和中风风险建立了联系。 同样，睡眠不足会导致促炎细胞因子增加3倍，从而导致 SWA的稳态驱动。此外，长期睡眠不足会导致慢性神经炎症级联反应 包括星形胶质细胞增生和小胶质细胞活化。总之，这些数据表明，CVRF和睡眠不足可能 部分通过神经炎症反应促进Aβ沉积。总体目标项目2 是为了了解星形胶质细胞增生作为神经炎症的标志物在 健康风险因素（CVRF和睡眠）和AD病理生理学的轨迹。在300名参与者中，我们将 完整的纵向评估：1）CVRF和睡眠效率以及SWA的临床血管测量 2）使用PET（SMBT-I）和血浆（GFAP）的星形胶质细胞增生;和 3)AD病理学包括Aβ-PET、血浆Aβ、tau PET和血浆tau。我们将研究横截面和 CVRF和睡眠与病理学的纵向关联以及星形胶质细胞增生的介导作用。我们将 探索CVRF、睡眠和星形胶质细胞增生的变化是否先于AD病理学的积累。

Project 2 Summary/Abstract Health risk factors such as cardiovascular risk factors (CVRF) and poor sleep are thought to increase the risk of Alzheimer’s disease (AD). While the mechanisms linking CVRF and poor sleep with AD pathology remain unclear, neuroinflammation such as astrogliosis, may be one such pathway. CVRF has consistent links to AD pathology: during the past 10 years of this program project, we explored the relationship of Aβ deposition alone and in combination with vascular modulators to neuronal dysfunction, and their association with progression to cognitive impairment and AD. We identified associations of increased arterial stiffness, systolic blood pressure, and cholesterol homeostasis with increases in Aβ burden In addition to CVRF, sleep is implicated as a risk factor for AD. Sleep has well-established links to brain structures and pathways implicated in AD, and is essential to cognitive, immune, and other physiological functions. Age- and disease-related sleep changes may influence the accumulation of AD pathology21, 22. Sleep loss is associated with increased levels of Aβ in the interstitial space, and influences kinetics of Aβ and tau in the cerebrospinal fluid. We and others have demonstrated that poor sleep quality and lower objective sleep efficiency (see preliminary data) are associated with greater Aβ burden. Moreover, through this program project, we found a stronger association between Aβ and forgetting in those with poorer sleep efficiency. Together, these data suggest that CVRF and poor sleep may create a state of vulnerability to AD pathology. Nonetheless, the mechanisms by which these health factors can create this increased vulnerability to AD remain unclear. One potential mediating factor is neuroinflammation. Cellular inflammation plays a well- established role in AD pathology. Inflammation has established links with CVRF, hypertension, and stroke risk. Similarly, sleep loss induces a 3-fold increase in pro-inflammatory cytokines, which contribute to the homeostatic drive for SWA. Moreover, chronic poor sleep leads to a cascade of chronic neuroinflammation including astrogliosis and microglial activation. Together, these data suggest that CVRF and poor sleep may accelerate the process of Aβ deposition partially through neuroinflammation. The overarching goal Project 2 is to understand the role of astrogliosis, as a marker of neuroinflammation, in the relationship between health risk factors (CVRF and sleep) and the trajectory of AD pathophysiology. In 300 participants we will complete longitudinal assessments of: 1) Clinical vascular measures of CVRF and sleep efficiency and SWA assessed with actigraphy and polysomnography; 2) Astrogliosis using PET (SMBT-1) and plasma (GFAP); and 3) AD pathology including Aβ-PET, plasma Aβ, tau PET, and plasma tau. We will examine cross-sectional and longitudinal associations of CVRF and sleep with pathology and the mediating role of astrogliosis. We will explore whether changes in CVRF, sleep, and astrogliosis precede accumulation of AD pathology.