Age-sex-ApoE allele interactions in neuronal and white matter vulnerability to air pollution

年龄-性别-ApoE等位基因相互作用影响神经元和白质对空气污染的脆弱性

基本信息

批准号：
10456754
负责人：
CALEB E FINCH
金额：
$ 30.93万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456754
关键词：
Age Aging Air Pollution Alleles Alzheimer&apos s disease risk Amyloid Amyloidosis Angiography Anisotropy Apolipoprotein E Atrophic Biological Assay Blood - brain barrier anatomy Brain C57BL/6 Mouse C57BL/6N Mouse CD36 gene Cerebral Ischemia Cerebrum Chemicals Chronic Classification Clinical Cognition Cognitive aging Cognitive deficits Collaborations Confocal Microscopy Core-Binding Factor Cytology Data Deposition Dose Elderly Experimental Models Exposure to Female Finches Genes Heterogeneity Hippocampus (Brain)Histocytochemistry Homozygote Hour Human IL6 gene Image Immunohistochemistry Impaired cognition In Vitro Inflammatory Inflammatory Response Ischemia Knock-out Knowledge Learning Magnetic Resonance Imaging Maps Mediating Modeling Monitor Mus Myelin Myelin Associated Glycoprotein Myelin Basic Proteins Nerve Degeneration Neurites Neurons Ovarian Cycles Particulate Matter Pathway interactions Perimenopause Pike fish Predisposition Process Reporting Resolution Risk Role Sampling TLR4 gene TNF gene Text Transgenic Mice Ultrafine Vagina Western Blotting Woman age related apolipoprotein E-4 blood-brain barrier disruption blood-brain barrier permeabilization cerebral hypoperfusion cerebrovascular cerebrovascular amyloid cohort community living cytotoxicity dementia risk experimental study familial Alzheimer disease fine particles high risk hippocampal subregions in vivo macrophage mouse model multiphoton imaging myelin degeneration nanoparticle nanosized neurotoxic premature reproductive senescence residence response sex synergism traffic-related air pollution white matter

项目摘要

Project 3 Abstract: Caleb Finch, with Todd Morgan and Christian Pike Age-Sex-ApoE Allele Interactions in White Matter Vulnerability to Air Pollution. To reviewers: new text is italicized. Accelerated cognitive aging is strongly associated with air pollution fine- sized particulate matter (PM2.5u) in two recent reports of community-living elderly 1, 2). Besides cognitive deficits and loss of white matter, the WHIMS cohort incurred higher risk of dementia (Project 1). In mouse models, nano-sized PM (nPM) from traffic-related air pollution (TRAP-nPM) is pro- amyloidogenic. In our experimental model, mice receive whole body exposure to TRAP-nPM for 150 hours intermittently during 10 weeks (Core C2). Besides brain-wide inflammatory responses, TRAP-nPM causes selective damage to hippocampal CA1 myelinated neurons (Fig. 4) that are most vulnerable in AD and to cerebrovascular ischemia. Because AD risk is elevated in women, particularly in apoE4 carriers, we propose to study age-sex-ApoE allele interactions in the vulnerability of myelinated pathways to nPM using EFAD mice. We also examine the blood-brain barrier (BBB), which shows greater age-related leakiness in human ApoE4 carriers. New data show that nPM increases activity in a TLR4 inflammatory pathway that mediates post- ischaemic neurodegeneration. We hypothesize that TRAP increases AD risk by TLR4-related inflammatory processes that synergize with CA1-specific hippocampal neurodegenerative mechanisms. Aim 1 (refocused): Age and sex in brain susceptibility of C57BL/6 (B6) mice to nPM. Both sexes of B6 mice will be exposed to nPM at ages 2 mo, 10, and 18 mo, spanning reproductive senescence. We will assay hippocampus mediated learning and hippocampal subregional analysis of myelin degeneration and neuron atrophy. Microglial and TLR4-TNFα pathway responses will be evaluated by immunohistochemistry and Western blots. Cerebrovascular and white matter tract responses to nPM exposure is assessed in Core B2 by in vivo multiphoton imaging for regional CBF and BBB permeability and angiography. DTI-MRI at 80µm isotropic spatial resolution will provide fractional anisotropy maps for white matter connectivity. BBB cellular integrity is assessed by confocal microscopy. Collaboration with Project 4 examines B6 brains for synergies of nPM with chronic cerebral hypoperfusion (CCH). Aim 2: Age-Sex-ApoE allele interactions in EFAD mouse responses to nPM. The Aim 1 parameters of age and sex for hippocampal-mediated learning and neurodegeneration in hippocampal subfields are examined in EFAD mice. Cerebrovascular amyloid and microbleeds will be evaluated in EFAD mice. We hypothesize that nPM will show female bias in accelerating AD changes. Aim 3 (major revisions): Role of TLR4. A new mouse model with inducible macrophage/microglial- specificTLR4 knockout (i-mTLR4-ko) will evaluate TLR4 contributions to nPM-induced myelin degeneration and neurite atrophy. This new model will identify targets of TLR4 pathway components in the effects of TRAP on myelinated pathways.

项目 3 摘要：Caleb Finch、Todd Morgan 和 Christian Pike 白质对空气污染脆弱性的年龄-性别-ApoE 等位基因相互作用。致审稿人：新文本是斜体的。加速认知老化与空气污染密切相关。最近两份关于社区老年人的报告中的颗粒物 (PM2.5u) 1, 2)。由于白质缺陷和损失，WHIMS 队列纳入了更高的痴呆风险（项目 1）。在小鼠模型中，交通相关空气污染 (TRAP-nPM) 产生的纳米级 PM (nPM) 会促进在我们的实验模型中，小鼠全身暴露于 TRAP-nPM 150 小时。在 10 周内间歇性地发生（核心 C2），除了全脑炎症反应外，TRAP-nPM 还会引起。海马 CA1 有髓鞘神经元的选择性损伤（图 4），这些神经元在 AD 中最脆弱，并且由于女性尤其是 apoE4 携带者患 AD 的风险较高，因此我们建议使用 EFAD 小鼠研究年龄-性别-ApoE 等位基因相互作用对 nPM 的有髓鞘通路的脆弱性。我们还检查了血脑屏障 (BBB)，该屏障显示人类 ApoE4 中与年龄相关的泄漏更大新数据表明，nPM 会增加介导后炎症通路的 TLR4 炎症通路的活性。我们勇敢地承认 TRAP 通过 TLR4 相关炎症增加 AD 风险。与 CA1 特异性海马神经退行性机制协同作用的过程。目标 1（重新聚焦）：C57BL/6 (B6) 小鼠的大脑对 nPM 的易感性的年龄和性别 B6 小鼠的两种性别都会。我们将在 2 个月、10 个月和 18 个月时暴露于 nPM，跨越生殖衰老。海马介导的学习以及髓磷脂变性和神经元的海马亚区域分析小胶质细胞和 TLR4-TNFα 通路反应将通过免疫组织化学进行评估。核心 B2 中评估脑血管和白质束对 nPM 暴露的反应。体内多光子成像，用于局部 CBF 和 BBB 渗透性以及 80 µm 的 DTI-MRI 血管造影。各向同性空间分辨率将为白质 BBB 细胞连接提供分数各向异性图。与 Project 4 合作检查 B6 大脑的协同作用来评估完整性。 nPM 伴有慢性脑灌注不足 (CCH)。目标 2：EFAD 小鼠对 nPM 反应中的年龄-性别-ApoE 等位基因相互作用目标 1 参数：年龄和海马介导的学习的性别和海马亚区的神经变性在将在 EFAD 小鼠中评估脑血管淀粉样蛋白和微出血。 nPM 将在加速 AD 变化方面表现出女性偏见。目标 3（重大修订）：TLR4 的作用，具有可诱导巨噬细胞/小胶质细胞的新小鼠模型。特异性TLR4敲除（i-mTLR4-ko）将评估TLR4对nPM诱导的髓磷脂变性的贡献这个新模型将确定 TLR4 通路成分的作用靶点。有髓鞘通路上的 TRAP。