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

项目3摘要：迦勒芬奇，与托德摩根和克里斯蒂安派克 白色物质对空气污染的易感性中的性别-ApoE等位基因相互作用 致审查者：新文本为斜体。认知老化加速与空气污染密切相关- 大小颗粒物（PM2.5u）在最近的两份报告中的社区生活的老年人1，2）。除了认知 由于白色物质的缺乏和损失，WHIMS队列发生痴呆的风险更高（项目1）。 在小鼠模型中，来自交通相关空气污染（TRAP-nPM）的纳米级PM（nPM）是有利的。 淀粉样变在我们的实验模型中，小鼠接受全身暴露于TRAP-nPM 150小时 在10周内间歇性地进行（核心C2）。除了全脑炎症反应，TRAP-nPM还导致 选择性损伤海马CA 1区有髓神经元（图4），这是最脆弱的AD和 脑血管缺血由于AD风险在女性中升高，特别是在apoE 4携带者中，我们建议 使用EFAD小鼠研究年龄-性别-ApoE等位基因在有髓鞘通路对nPM的脆弱性中的相互作用。 我们还检查了血脑屏障（BBB），它显示了人类ApoE 4中与年龄相关的更大的泄漏。 载波新的数据表明，nPM增加了TLR 4炎症通路的活性，该通路介导了炎症后的炎症反应。 缺血性神经变性我们假设TRAP通过TLR 4相关的炎症反应增加AD的风险。 与CA 1特异性海马神经退行性机制协同作用的过程。 目的1（重新聚焦）：C57 BL/6（B6）小鼠对nPM的脑易感性中的年龄和性别。两种性别的B6小鼠将 在2月龄、10月龄和18月龄暴露于nPM，跨越生殖衰老。我们将分析 海马介导学习及髓鞘变性和神经元海马亚区分析 萎缩将通过免疫组织化学评价小胶质细胞和TLR 4-TNFα通路反应， Western印迹。在核心B2中，通过以下方式评估脑血管和白色束对nPM暴露的反应： 用于局部CBF和BBB渗透性和血管造影的体内多光子成像。DTI-MRI（80µm） 各向同性空间分辨率将为白色物质连通性提供分数各向异性图。BBB细胞 通过共聚焦显微镜评价完整性。与项目4的合作研究了B6大脑的协同作用， 慢性脑灌注不足（CCH）。 目的2：EFAD小鼠对nPM反应中的性别-ApoE等位基因相互作用。Aim 1年龄参数和 性别对海马介导的学习和海马亚区的神经变性的影响 EFAD小鼠。将在EFAD小鼠中评价脑血管淀粉样蛋白和微出血。我们假设 nPM将显示女性在加速AD变化方面的偏好。 目标3（主要修订）：TLR 4的作用。一种新的具有可诱导的巨噬细胞/小胶质细胞的小鼠模型- 特异性TLR 4敲除（i-mTLR 4-ko）将评估TLR 4对nPM诱导的髓鞘变性的贡献 和神经突萎缩这种新的模型将确定TLR 4通路组分的靶点， 有髓鞘通路上的TRAP。

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.