Air Pollution and vulnerability to Alzheimer-like neurodegeneration in mice

描述（申请人提供）：空气污染可能加速大脑老化。中年人的流行病学研究表明，空气污染的局部差异与认知能力下降的加速有关（Chen & Schwartz 2010），而来自高度污染的墨西哥城市的年轻人的大脑中弥散性淀粉样蛋白和神经胶质炎症激活的过早沉积在apoE4携带者中更为严重（Block & Calderon-Garciduenas 2009）。相应的暴露于交通产生的纳米颗粒材料（nPM）的啮齿动物模型显示出神经胶质炎症变化。我们的试点数据显示，暴露于nPM 10周激活了神经胶质细胞，并改变了体内和体外的神经元谷氨酸能受体。我们建议分析nPM对J20-ADtg小鼠和具有更广泛AD样神经病理的三重转基因AD小鼠（3xTg-AD）的神经胶质炎症、淀粉样变性和神经退行性变的影响。我们还将使用体外模型验证nPM促进Abeta42产生并加剧Abeta42诱导的毒性的假设。

DESCRIPTION (provided by applicant): Air pollution may accelerate brain aging. Epidemiological studies of the middle-age have shown accelerated cognitive decline in association with local differences in air pollution (Chen & Schwartz 2010), while brains of young adults from a highly polluted Mexican city had premature deposits of diffuse amyloid and glial inflammatory activation which were greater in apoE4 carriers (Block & Calderon-Garciduenas 2009). Corresponding rodent models with defined exposure to traffic-generated nano-sized particulate material (nPM) have shown glial inflammatory changes. Our pilot data show that exposure to nPM for 10 weeks activated glia and altered neuronal glutamatergic receptors in vivo and in vitro. We propose to analyze effects of nPM on glial inflammation, amyloidogenesis, and neurodegeneration in J20-ADtg mice and in triple transgenic AD mice (3xTg-AD), which has more extensive AD-like neuropathology. We will also test the hypotheses that nPM promotes Abeta42 production and exacerbates Abeta42-induced toxicity using in vitro models. PUBLIC HEALTH RELEVANCE: These novel studies will use mouse models to define the neurodegenerative pathways of urban airborne nano-sized particulate matter (nPM). We will evaluate the hypothesis that nPM causes neural damage through shared pathways with amyloid-beta. Identification of mechanisms and of relevant biomarkers in nPM toxicology is essential for development of broad-spectrum interventions.