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

项目3摘要：凯勒·芬奇，托德·摩根和克里斯蒂安·派克 白质易受空气污染影响的年龄-性别-载脂蛋白E等位基因交互作用。 致审稿人：新文本以斜体显示。认知老化加速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大小颗粒物(PM2.5u)1，2)。除了认知 在脑白质缺失和丢失的情况下，突发奇想的人群患痴呆症的风险更高(项目1)。 在小鼠模型中，交通相关空气污染引起的纳米颗粒物(NPM)是有利的 淀粉样变性。在我们的实验模型中，小鼠接受了150小时的TRAP-NPM全身暴露 间歇性地在10周内(核心C2)。除了全脑炎症反应外，TRAP-NPM还导致 选择性损伤海马CA1区有髓神经元(图4)，这些神经元在AD和 脑血管缺血。由于AD风险在女性中升高，特别是在载脂蛋白E4携带者中，我们建议 利用EFAD小鼠研究年龄-性别-载脂蛋白E等位基因的交互作用对NPM易感性的影响。 我们还检查了血脑屏障(BBB)，它显示出人类载脂蛋白E4与年龄相关的更大的渗漏 承运人。新数据显示，NPM增加了TLR4炎症途径的活性，该途径介导了 缺血性神经退行性变。我们假设TRAP通过与TLR4相关的炎症增加AD的风险 与CA1特异性海马神经退行性变机制协同的过程。 目的1(重新聚焦)：C57BL/6(B6)小鼠对NPM易感性的年龄和性别。B6小鼠的两性都会 在2个月、10个月和18个月龄时暴露于NPM，持续生殖衰老。我们将进行化验 海马区介导的学习与髓鞘变性和神经元的海马区分析 萎缩。小胶质细胞和TLR4-肿瘤坏死因子α途径的反应将通过免疫组织化学和 西式印迹。在核心B2中评估脑血管和白质束对NPM暴露的反应 活体多光子成像检测局部脑血流量和血脑屏障通透性及血管造影。80微米DTI-MRI 各向同性空间分辨率将为白质连通性提供分数各向异性图。血脑屏障细胞 完整性通过共聚焦显微镜进行评估。与Project 4的合作检查B6大脑的协同效应 NPM合并慢性脑低灌注(CCH)。 目的2：年龄-性别-载脂蛋白E等位基因在EFAD小鼠对NPM反应中的相互作用。目标1年龄和年龄的参数 性别对海马体介导的学习和海马区神经退行性变的研究 EFAD小鼠。脑血管淀粉样蛋白和微量出血将在EFAD小鼠中进行评估。我们假设 NPM将在加速AD变化方面显示出女性偏见。 目标3(主要修订)：TLR4的作用。一种新的小鼠巨噬细胞/小胶质细胞诱导模型 特异性TLR4基因敲除(I-mTLR4-Ko)将评估TLR4在NPM诱导的髓鞘变性中的作用 和轴突萎缩。这一新模型将确定TLR4通路组件的靶点。 困在有髓鞘的通路上。

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.