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

 描述（由申请人提供）：淀粉样蛋白和炎症：apoE、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。最高AD风险组，女性apoE 4携带者，在携带家族性显性AD基因与人类apoE等位基因（靶向替代，ApoE-TR）组合的EFAD小鼠中建模。雌性E4 FAD小鼠具有最多的脑细胞因子诱导、淀粉样肽（Abeta）积累和微出血（试点数据）。在人类中，脑微出血在apoE 4携带者中最普遍，并且与向临床AD的较高转化相关。在环境对认知老化和AD的影响中，城市空气污染也被认为是一个实验模型，其中包含来自城市交通空气走廊的纳米级颗粒物（nPM）（与共同研究者Constantinos Sioutas）。将充分表征的组合物的nPM再雾化用于小鼠的受控暴露。初步数据显示EFAD小鼠对apoE等位基因特异性有反应。目的1：探讨出生后发育和衰老过程中AD表型中性别-apoE等位基因相互作用的年龄表。将研究EFAD脑的炎症反应（TNF α，小胶质细胞）; APP加工和Abeta沉积;脑血管淀粉样蛋白和微出血;以及空间记忆（与Christian Pike，共同研究者）。性别差异将通过新生儿类固醇治疗来控制，以检验以下假设：在任一遗传性别中，Abeta的过度表达将驱动炎症和微出血的水平。将在体外研究EFAD小胶质细胞对炎症基因表达的apoE-性别相互作用。目的2通过剂量和时间考察空气污染nPM对雌性EFAD小鼠脑炎症和AD表型的加速作用。将检查AD表型的nPM暴露临界年龄，目标1的最早年龄结果显示AD表型的性别差异。我们只能测试一种性别，因为nPM处理使变量数量加倍。我们在这一目标中优先考虑女性，因为女性是AD风险最高的群体。然而，来自成年大脑的小胶质细胞和神经元的体外研究将包括两种性别的nPM诱导的炎症和促淀粉样蛋白生成反应。目的3通过一种新的γ分泌酶调节剂来检测用于脑炎症和微出血的药物干预以减弱Abeta合成。将药物处理的雌性EFAD小鼠暴露于慢性nPM，并检查apoE对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.