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（适用提供）：淀粉样蛋白和注射：APOE，性别，空气污染和药物的调节。我们建议在小鼠模型中测试针对脑淀粉样蛋白和微淀粉样蛋白和微生物的新型感染性别 - 环境相互作用，以实现阿尔茨海默氏病（AD）和衰老的小鼠模型。最高的AD风险组，女性APOE4载体，在携带家庭主导AD基因的EFAD小鼠中建模，并与人类APOE等位基因结合使用（靶向替换，APOE-TR）。雌性E4FAD小鼠具有最多的脑细胞因子诱导，淀粉样蛋白肽（ABETA）的积累和微粒（Pilot Data）。在人类中，脑微粒在APOE4载体中最普遍，并且与较高的转化为临床AD有关。在对认知衰老和AD的环境影响中，城市空气污染也被考虑到来自城市交通空气走廊的纳米级特殊物质（NPM）的实验模型（constantinos sioutas，cole-Investigator）。良好特征的组合物的NPM被重新涂层以控制小鼠的控制。试验数据显示，EFAD小鼠对APOE等位基因特异性做出了反应。 AIM 1解决了产后发展和衰老期间AD表型中性别 - APOE等位基因相互作用的年龄表。 EFAD大脑将研究炎症反应（TNFA，小胶质细胞）；用于应用程序处理和ABETA存款；用于脑血管淀粉样蛋白和微粒；以及用于空间记忆（与基督教派克（Christian Pike），共同研究器）。新生儿立体治疗将操纵性别差异，以检验超过Abeta表达的假设，即在任何一种遗传性别中，都会驱动炎症和微粒体的水平。在体外，将研究EFAD小胶质细胞在炎症基因表达上的APOE-性相互作用。 AIM 2考试通过剂量和加速脑感染和AD表型的时间和时间对女性EFAD小鼠的空气污染NPM效应。 NPM暴露于AD-型的关键年龄将通过AIM 1的发现，最早显示出AIM 1的发现，显示出AD-典型型的性别差异。我们只能测试一种性别，因为NPM治疗将变量的数量增加一倍。我们在此目标中优先考虑女性，因为女性是广告风险最高的群体。然而，对成年大脑的小胶质细胞和神经元的体外研究将包括NPM诱导的炎症和促淀粉样蛋白原反应的性别。 AIM 3检查了新型伽玛泌尿酶调节剂对脑注射的药物干预，以减轻ABETA合成。药物治疗的雌性EFAD小鼠将暴露于慢性NPM中，并检查APOE在AD-PHENOTYPES上的相互作用。

项目成果

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。

• DOI: 10.1016/j.atmosenv.2019.117197
• 发表时间: 2020
• 期刊: Atmospheric environment (Oxford, England : 1994)
• 作者: Pirhadi,Milad;Mousavi,Amirhosein;Taghvaee,Sina;Shafer,MartinM;Sioutas,Constantinos
• 通讯作者: Sioutas,Constantinos

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。

• DOI: 10.1523/eneuro.0077-17.2017
• 发表时间: 2017
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Moser,VAlexandra;Pike,ChristianJ
• 通讯作者: Pike,ChristianJ

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

• DOI: 10.1016/j.neurobiolaging.2018.09.016
• 发表时间: 2019-01
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Moser VA;Christensen A;Liu J;Zhou A;Yagi S;Beam CR;Galea L;Pike CJ
• 通讯作者: Pike CJ

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

• DOI: 10.1016/j.atmosenv.2018.06.016
• 发表时间: 2018-09
• 期刊: Atmospheric environment (Oxford, England : 1994)
• 作者: Lovett C;Sowlat MH;Saliba NA;Shihadeh AL;Sioutas C
• 通讯作者: Sioutas C

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。

• DOI: 10.12688/f1000research.15445.2
• 发表时间: 2018
• 期刊: F1000Research
• 作者: Lovett,Christopher;Baasiri,Mohamad;Atwi,Khairallah;Sowlat,MohammadH;Shirmohammadi,Farimah;Shihadeh,AlanL;Sioutas,Constantinos
• 通讯作者: Sioutas,Constantinos