The effect of circadian rhythm disruptions on the angiogenic response to hypoperfusion in the AD brain

项目摘要/摘要 尽管阿尔茨海默病(AD)的病理生理学是复杂和多因素的，但血管并发症 几乎三分之二的AD患者会出现脑血管功能不全。然而，脑血管 缺乏与阿尔茨海默病的相互作用和对AD的贡献仍然知之甚少。最近，脑血管小体(即 脑内皮细胞和周细胞的转录组图谱)被认为是一个概念性的 研究中枢神经系统疾病血管机制的框架。针对RFA-AG-23-014(机制 AD/ADRD的脑低灌注率)，我们建议检验脑血管功能不全的假设 扰乱AD的脑血管，最终导致认知障碍。 正常大脑通过诱导内源性血管重塑和 血管生成。AD的存在干扰了内源性血管生成和血管恢复 到低灌注量，这会加剧AD的进展，恶化AD的脑血管。因为 已知昼夜节律和昼夜节律基因调节血管生成，我们进一步假设AD 破坏脑血管的昼夜动态平衡，从而干扰内源性血管生成 对低灌注率的反应。 研究AD、血管反应和昼夜节律之间的这些相互作用的重要性是 由我们的试点数据强调。例如，我们发现大脑的转录组图谱有较大的差异 比较野生型与AD小鼠活跃期(清醒)时内皮细胞和周细胞的变化 进入非活动(睡眠)阶段。为了验证我们的假设，我们提出了三个综合目标。《目标1》将展示 AD大脑表现出较低的代偿性血管生成能力，以应对低灌流，目标2 将表明AD大脑中的昼夜节律被打乱，而被打乱的昼夜节律被抑制 血管生成反应。最后，目标3将研究重新正常化昼夜节律是否会改善 脑血管构筑并促进AD小鼠低灌流后的血管生成。 AD脑是否以及如何在脑低灌流后丧失代偿性血管生成能力尚不清楚。 因此，我们设计了一个多学科、多实验室的项目，通过研究如何填补这一知识缺口 昼夜节律的扰动扰乱了脑血管，加重了AD患者的低灌注率。

PROJECT SUMMARY/ABSTRACT Although the pathophysiology of Alzheimer’s Disease (AD) is complex and multifactorial, vascular comorbidities and cerebrovascular insufficiency occur in almost two-thirds of AD patients. However, how cerebrovascular insufficiency interacts with and contributes to AD remains poorly understood. Recently, the brain vasculome (i.e. transcriptome profiles of cerebral endothelial cells and pericytes) has been proposed as a conceptual framework to investigate vascular mechanisms in CNS diseases. In response to RFA-AG-23-014 (Mechanisms of Brain Hypoperfusion in AD/ADRD), we propose to test the hypothesis that cerebrovascular insufficiency perturbs the AD brain vasculome, eventually leading to cognitive impairment. The normal brain compensates for hypoperfusion by inducing endogenous vascular remodeling and angiogenesis. The presence of AD interferes with endogenous angiogenesis and vascular recovery in response to hypoperfusion, and this exacerbates AD progression and worsens the AD brain vasculome. Because circadian rhythms and circadian genes are known to regulate angiogenesis, we further hypothesize that AD disrupts circadian homeostasis in the brain vasculome, thus interfering with the endogenous angiogenic response to hypoperfusion. The importance of investigating these interactions between AD, vascular responses, and circadian rhythms is emphasized by our pilot data. For example, we show a greater difference in transcriptome profiles of cerebral endothelial cells and pericytes of wild-type vs AD mice when tested during the active (awake) phase compared to the inactive (sleep) phase. For testing our hypotheses, we propose three integrated aims. Aim 1 will show that AD brains exhibit a lower capacity of compensatory angiogenesis in response to hypoperfusion, and Aim 2 will show that circadian rhythms are disrupted in AD brains and that disrupted circadian rhythms suppress angiogenic response. And finally, Aim 3 will examine whether re-normalizing circadian rhythms improves the brain vasculome and promotes angiogenesis after hypoperfusion in AD mice. Whether and how AD brains lose compensatory angiogenesis capacity after cerebral hypoperfusion is unknown. Therefore, we have designed a multi-disciplinary multi-lab project to fill this gap of knowledge by examining how perturbations in circadian rhythms disrupt the brain vasculome and worsen hypoperfusion in AD.