Amyloid and inflammation: modulation by apoE, gender, air pollution, and drugs

 描述(申请人提供)：淀粉样蛋白和炎症：受载脂蛋白E、性别、空气污染和药物的调节。我们建议在阿尔茨海默病(AD)和衰老的小鼠模型中测试新的炎症-性别-环境相互作用对脑淀粉样蛋白和微出血(微出血)的影响。AD风险最高的人群，女性apoE4携带者，是在携带家族显性AD基因和人类apoE等位基因(靶向替换，apoE-tr)的EFAD小鼠中建模的。雌性E4FAD小鼠具有最多的脑细胞因子诱导、淀粉样肽(Abeta)积聚和微出血(试点数据)。在人类中，脑微出血在apoE4携带者中最常见，并与较高的临床AD转换率有关。在环境对认知老化和AD的影响中，城市空气污染也被考虑在一个实验模型中，该模型使用来自城市交通空气走廊的纳米颗粒物(NPM)(与Constantinos Sioutas共同研究)。将特征良好的NPM重新雾化，以控制小鼠的暴露。试点数据显示，EFAD小鼠的反应具有apoE等位基因特异性。目的1研究出生后发育和衰老过程中AD表型性别-载脂蛋白E等位基因交互作用出现的年龄规律。EFAD大脑将被研究炎症反应(TNFa，小胶质细胞)；APP处理和Abeta沉积；脑血管淀粉样蛋白和微出血；以及空间记忆(与克里斯蒂安·派克共同研究)。性别差异将通过新生儿类固醇治疗来检验这一假设，即无论是哪种基因性别，Abeta的过度表达都会导致炎症和微出血的水平。在体外，EFAD小胶质细胞将被研究载脂蛋白E-性相互作用对炎症基因表达的影响。目的2研究空气污染对雌性EFAD小鼠脑部炎症和AD表型的影响。AD表型的NPM暴露的临界年龄将与目标1中显示AD表型性别差异的最早年龄的结果一起进行检查。我们只能测试一种性别，因为NPM治疗使变量数量翻了一番。我们在这个目标中优先考虑女性，因为女性是AD风险最高的群体。然而，对来自成人大脑的小胶质细胞和神经元的体外研究将包括两性对NPM诱导的炎症和淀粉样原原反应的影响。目的3研究一种通过一种新型的伽马分泌酶调节剂抑制Abeta合成来治疗脑部炎症和微出血的药物干预。药物治疗的雌性EFAD小鼠将暴露在慢性NPM中，并检查载脂蛋白E与AD表型的相互作用。

 DESCRIPTION (provided by applicant): Amyloid and inflammation: modulation by apoE, gender, air pollution, and drugs. We propose to test novel inflammation-gender-environment interactions on brain amyloid and microbleeds (microhemorrhages) in mouse models for Alzheimer disease (AD) and aging. The highest AD risk group, women apoE4 carriers, is modelled in EFAD mice carrying familial dominant AD genes in combination with human apoE alleles (targeted replacement, ApoE-TR). Female E4FAD mice have the most brain cytokine induction, amyloid peptide (Abeta) accumulation, and microbleeds (pilot data). In humans, cerebral microbleeds are most prevalent in apoE4 carriers, and are associated with higher conversion to clinical AD. Among environmental influence on cognitive aging and AD, urban air pollution is also considered in an experimental model with nano-scale particulate matter (nPM) from an urban traffic air corridor (with Constantinos Sioutas, co-Investigator). The nPM of well-characterized composition are re-aerosolized for controlled exposure of mice. Pilot data show EFAD mice respond with apoE allele specificity. Aim 1 addresses the age schedule of emergence of gender-apoE allele interactions in AD phenotypes during postnatal development and aging. EFAD brains will be studied for inflammatory responses (TNFa, microglia); for APP processing and Abeta deposits; for cerebrovascular amyloid and microbleeds; and for spatial memory (with Christian Pike, co-Investigator). Sex differences will be manipulated by neonatal steroid treatment to test the hypothesis that excess expression of Abeta, in either genetic sex, will drive the level of inflammation and microbleeds. In vitro, EFAD microglia will be studied for apoE-sex interactions on inflammatory gene expression. Aim 2 examines air pollution nPM effects in female EFAD mice by dose and time on accelerating brain inflammation and AD phenotypes. Critical ages of nPM exposure for AD-phenotypes will be examined with findings from Aim 1 for the earliest age showing gender differences in AD-phenotypes. We can only test one sex because nPM treatment doubles the number of variables. We prioritize females in this aim since females are the highest AD risk group. However, in vitro studies of microglia and neurons from adult brains will include both sexes for nPM induced inflammatory and pro-amyloidogenic responses. Aim 3 examines a drug intervention for brain inflammation and microbleeds by a novel gamma secretase modulator to attenuate Abeta synthesis. Drug-treated female EFAD mice will be exposed to chronic nPM and examined for apoE interactions on AD-phenotypes.