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

淀粉样蛋白和炎症：apoE、性别、空气污染和药物的调节

• 批准号: 9001756
• 负责人: CALEB E FINCH
• 金额: $ 303.57万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001756
• 关键词: Abeta synthesis; Address; Adult; Age; Aging; Air; Air Pollution; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Attenuated; Behavior; Biological Assay; Blood Vessels; Brain; Cerebral cortex; Chronic; Clinical; Cognition; Cognitive aging; Cognitive deficits; Data; Defect; Deposition; Development; Dose; Encephalitis; Environment; Environmental Risk Factor; Experimental Designs; Experimental Models; Female; Feminization; Finches; Fossil Fuels; Gender; Gene Expression; Genes; Genetic; Glutamate Receptor; Glutamates; Gonadal Steroid Hormones; Hemoglobin; High Prevalence; Hippocampus (Brain); Human; Human Genetics; IL6 gene; Impaired cognition; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intervention; Mediating; Microglia; Modeling; Molecular; Mus; Neonatal; Neurons; Particulate; Particulate Matter; Passive Immunization; Pharmaceutical Preparations; Pike fish; Puberty; Reporting; Research Personnel; Risk Factors; Rodent; Role; Schedule; Sex Characteristics; Specificity; Steroids; TLR4 gene; Testing; Time; Transgenic Mice; Woman; Women' s Group; abeta accumulation; aerosolized; air filter; amyloid peptide; amyloid precursor protein processing; apolipoprotein E-4; cerebral microbleeds; cerebrovascular amyloid; cytokine; density; disease phenotype; endotoxin receptor; familial Alzheimer disease; gamma secretase; genetic risk factor; in vivo; inflammatory marker; male; mouse model; nanoscale; nanosized; novel; postnatal; public health relevance; receptor function; response; sex; spatial memory; trafficking

 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.

 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）小鼠模型中测试大脑淀粉样蛋白和微出血（微出血）的新型炎症-性别-环境相互作用。 ）和衰老是 AD 风险最高的群体，即女性 apoE4 携带者，在携带家族显性 AD 基因与人类 apoE 等位基因（靶向替换、 ApoE-TR）。雌性 E4FAD 小鼠的脑细胞因子诱导、淀粉样肽 (Abeta) 积累和微出血最多（试点数据）。在环境对认知老化和 AD 的影响中，城市空气污染也在一个实验模型中得到考虑，该模型使用来自城市交通空中走廊的纳米级颗粒物 (nPM)（与 Constantinos Sioutas 合作，共同研究者）将已充分表征的组合物重新雾化以控制小鼠的暴露，试验数据显示 EFAD 小鼠对 apoE 等位基因特异性做出反应，目标 1 解决了 AD 表型中性别-apoE 等位基因相互作用的出现的年龄时间表。在出生后发育和衰老过程中，将研究 EFAD 大脑的炎症反应（TNFa、小胶质细胞）；以及脑血管淀粉样蛋白的 Abeta 沉积；微出血；以及空间记忆（与合作研究员克里斯蒂安·派克一起）将通过新生儿类固醇治疗来控制性别差异，以检验无论遗传性别中 Abeta 的过度表达都会驱动炎症和微出血水平的假设。在体外，将研究 EFAD 小胶质细胞的 apoE-性别相互作用对炎症基因表达的影响，目标 2 通过剂量和时间检查空气污染 nPM 对雌性 EFAD 小鼠加速脑炎症和 AD 表型的影响。将使用目标 1 的结果来检查 AD 表型的 nPM 暴露年龄，以了解 AD 表型中显示性别差异的最早年龄。我们只能测试一种性别，因为 nPM 治疗使变量数量增加了一倍，因为我们在此目标中优先考虑女性。然而，针对成人大脑小胶质细胞和神经元的体外研究将包括男性和女性的 nPM 诱导的炎症和促淀粉样蛋白生成反应，目的 3 检查药物干预对大脑炎症和微出血的影响。药物治疗的雌性 EFAD 小鼠将被暴露于慢性 nPM 中，并检查 apoE 对 AD 表型的相互作用。

项目成果

Obesity Accelerates Alzheimer-Related Pathology in APOE4 but not APOE3 Mice.

肥胖会加速 APOE4 小鼠的阿尔茨海默病相关病理，但不会加速 APOE3 小鼠。

• 发表时间: 2017
• 影响因子: 3.4
• 作者: Moser, V Alexandra;Pike, Christian J
• 通讯作者: Pike, Christian J

Effects of aging, high-fat diet, and testosterone treatment on neural and metabolic outcomes in male brown Norway rats.

衰老、高脂肪饮食和睾酮治疗对雄性棕色挪威大鼠神经和代谢结果的影响。

• 发表时间: 2019-01
• 影响因子: 4.2
• 作者: Moser, V Alexandra;Christensen, Amy;Liu, Jiahui;Zhou, Amanda;Yagi, Shunya;Beam, Christopher R;Galea, Liisa;Pike, Christian J
• 通讯作者: Pike, Christian J

Semi-volatile components of PM2.5 in an urban environment: volatility profiles and associated oxidative potential.

城市环境中 PM2.5 的半挥发性成分：挥发性特征和相关的氧化潜力。

• 发表时间: 2020-02-15
• 作者: Pirhadi, Milad;Mousavi, Amirhosein;Taghvaee, Sina;Shafer, Martin M;Sioutas, Constantinos
• 通讯作者: Sioutas, Constantinos

Comparison of the oxidative potential of primary (POA) and secondary (SOA) organic aerosols derived from α-pinene and gasoline engine exhaust precursors.

源自α-蒎烯和汽油发动机废气前体的初级（POA）和次级（SOA）有机气溶胶的氧化电位比较。

• 发表时间: 2018
• 作者: Lovett, Christopher;Baasiri, Mohamad;Atwi, Khairallah;Sowlat, Mohammad H;Shirmohammadi, Farimah;Shihadeh, Alan L;Sioutas, Constantinos
• 通讯作者: Sioutas, Constantinos

Oxidative Potential of Ambient Particulate Matter in Beirut during Saharan and Arabian Dust Events.

撒哈拉和阿拉伯沙尘事件期间贝鲁特环境颗粒物的氧化电位。

• DOI: 10.1016/j.atmosenv.2018.06.016
• 发表时间: 2018-09
• 期刊: Atmospheric environment
• 影响因子: 5
• 作者: Lovett C;Sowlat MH;Saliba NA;Shihadeh AL;Sioutas C
• 通讯作者: Sioutas C