Do Atmospheric Ultrafine Particles Lodge in the Brain and Cause Cognitive Decline Leading to Alzheimer's Disease Related Dementias?

项目摘要 越来越多的人认为环境因素影响阿尔茨海默病和老年痴呆症的风险 疾病相关性痴呆（AD/ADRD）。与这一假设相一致，参与者的认知轨迹 加州大学戴维斯分校阿尔茨海默病研究中心（UCD ADRC）纵向多样性队列（LDC） 地理上。这些地理差异可能是由于对环境的不同暴露造成的。 污染物。在这项转化研究中，我们将测试我们的中心假设，即超细颗粒物 （UFPM）进入暴露个体的大脑，增加认知能力下降和AD/ADRD事件的风险。 人类和动物研究主要集中在PM2.5（空气动力学直径为 < 2.5 µm）。UFPM是PM2.5的一个子集。由于其尺寸较小（< 0.1 µm），吸入UFPM 可以跨越生物屏障进入多个器官，包括大脑。我们之前的工作发现UFPM 在暴露于交通相关空气污染（TRAP）的大鼠大脑中，而不是过滤空气对照，表明UFPM 可能是脑损伤的一种机制到目前为止，还没有人类研究和动物研究专门关注 AD/ADRD中的UFPM。与大多数空间上相对均匀的空气污染物不同，UFPM 集中在污染源附近，因此它们在地理上是离散的。为了验证我们的假设，我们将利用 UCD独有的资源：（1）LDC，它已经在北方加州对500个人进行了地理编码， 人口普查区水平与相关的纵向认知措施;（2）神经病理学样本的一些 这些人，（3）UFPM暴露模型，量化特定空气污染物的水平和来源， 2000年至2019年最不发达国家捕获面积;（4）暴露于不变环境的大鼠含有UFPM的大脑 真实的时间的TRAP;以及（5）用于表征化学组成的高光谱和拉曼光谱 UFPM在大鼠和人脑中的分布，以评估大脑分布并进一步了解来源。利用这些资源， 我们将致力于以下目标：1。鉴定暴露于TRAP的TgF 344-AD大鼠脑中UFPM的来源 并评估UFPM与大鼠脑中AD相关神经病理学的空间关系。2.确定是否 人类暴露于UFPM与（a）偶发性认知损害和AD/ADRD相关，以及（B）加速 认知能力下降的速度。3.在人类AD/ADRD脑样本中启动探索性研究，以确定是否 LDC个体的选定脑区域中的UFPM与AD病理学相关。该项目的数据将确定 与UFPM相关的AD/ADRD相关神经病理学，发展机制假说的第一步 这可以在未来的研究中进行测试。此外，该项目还涉及（1）生物相容性和临床 UFPM在空气污染中作为改变AD/ADRD发生和进展的环境因素的相关性 并导致AD/ADRD种族/民族差异;（2）AD/ADRD大鼠模型与人类的相关性 暴露于污染空气中的UFPM;（3）生成支持公共卫生和监管所需的数据 控制与AD/ADRD相关的UFPM关键来源的战略。

Project Summary There is growing consensus that environmental factors influence risk for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). Consistent with this hypothesis, cognitive trajectories of participants in the UC Davis Alzheimer’s Disease Research Center (UCD ADRC) Longitudinal Diversity Cohort (LDC) differ geographically. These geographical differences may arise from differential exposures to environmental contaminants. In this translational study, we will test our central hypothesis that ultrafine particulate matter (UFPM) enters the brain of exposed individuals and increases risk of cognitive decline and incident AD/ADRD. Human and animal studies have largely focused on PM2.5 (fine particulate matter with an aerodynamic diameter < 2.5 µm) in AD/ADRD risk. UFPM is a subset of PM2.5. Because of its smaller size (< 0.1 µm), inhaled UFPM can cross biological barriers to gain access to multiple organs, including the brain. Our prior work found UFPM in the brain of rats exposed to traffic-related air pollution (TRAP), but not filtered air controls, indicating UFPM may be a mechanism of brain injury. To date, no human studies and few animal studies have focused specifically on UFPM in AD/ADRD. Unlike most air pollutants that are relatively spatially homogeneous, UFPM are more concentrated near pollutant sources, so they are geographically discrete. To test our hypothesis, we will leverage resources unique to UCD: (1) the LDC, which has already geocoded 500 individuals in Northern California at the census tract level with associated longitudinal cognitive measures; (2) neuropathological samples on some of these individuals, (3) an UFPM exposure model that quantifies levels and sources of specific air pollutants over the LDC capture area from 2000 to 2019; (4) brains containing UFPM from rats exposed to unchanged ambient TRAP in real time; and (5) hyperspectral and Raman spectroscopy for characterizing the chemical composition of UFPM in rat and human brains to assess brain distribution and further inform source. Using these resources, we will address the following Aims: 1. Identify the source of UFPM in brains of TgF344-AD rats exposed to TRAP and assess the spatial relationship of UFPM to AD-relevant neuropathology in rat brains. 2. Determine whether human exposure to UFPM is associated with (a) incident cognitive impairment and AD/ADRD and (b) accelerated rate of cognitive decline. 3. Initiate exploratory studies in human AD/ADRD brain samples to determine whether UFPM in select brain regions of LDC individuals are related to AD pathology. Data from this project will identify AD/ADRD-relevant neuropathology associated with UFPM, a first step in developing mechanistic hypotheses that can be tested in future studies. Additionally, this project addresses (1) biological plausibility and clinical relevance of UFPM in air pollution as an environmental factor that modifies AD/ADRD initiation and progression and contributes to AD/ADRD racial/ethnic disparities; (2) relevance of the AD/ADRD rat model to humans exposed to UFPM in polluted air; and (3) generation of data needed to support public health and regulatory strategies for controlling key sources of UFPM associated with AD/ADRD.