The role of microglia Nek6 in myocardial infarction-induced cognitive impairment

已有多项研究报道心力衰竭患者存在认知功能障碍。然而， 这背后的分子机制还不是很清楚。携带人类载脂蛋白4的小鼠，这是一个危险因素 对于患有心血管疾病的痴呆症患者，他们在出现心力衰竭后表现出认知障碍。 这些小鼠的小胶质细胞数量也比未断奶的非HF对照组小鼠高。这个 对学习和记忆至关重要的海马体高水平表达与疾病相关的小胶质细胞 TSPO和Tnfsf13b等基因。此外，心衰小鼠的小胶质细胞上调了Nek6的表达，而Nek6 使组蛋白H1和H3磷酸化，导致基因激活。根据这些初步数据，我们 心力衰竭小鼠小胶质细胞Nek6上调可加重炎症反应和损伤 认知功能。我们将在一个特定的目标上检验这一假设。我们将描述炎症在其中的作用 心力衰竭患者的认知障碍(目标1.1)。海马炎症、白细胞分布、小胶质细胞 激活，过量小胶质细胞的来源，淀粉样斑块沉积，小胶质细胞吞噬活性，以及 将评估TSPO对心力衰竭小鼠记忆障碍的影响。此外，Nek6在表观遗传学中的作用 将辨别心力衰竭小鼠海马区小胶质细胞的改变和记忆障碍(目标1.2)。

Various studies have reported that patients with heart failure (HF) have cognitive impairment. However, the molecular mechanisms behind this are not well understood. Mice carrying human APOE4, which is a risk factor for dementia in patients with cardiovascular disease, exhibited cognitive impairment after they developed HF. These mice also had heightened number of microglia compared to littermate non-HF control mice. The hippocampus, which is crucial to learning and memory, expressed high levels of disease-associated microglial genes such as Tspo and Tnfsf13b. Additionally, microglia in mice with HF upregulated Nek6, which phosphorylates histones H1 and H3, resulting in gene activation. Based on these preliminary data, we hypothesize that Nek6 upregulation in microglia in mice with heart failure exaggerates inflammation and impairs cognitive function. We will test this hypothesis in one specific aim. We will delineate the role of inflammation in cognitive impairment in HF (Aim 1.1). Hippocampal inflammation, distribution of leukocyte populations, microglial activation, source of excess microglia, amyloid plaque deposition, microglial phagocytic activity, and the role of Tspo in memory impairment in mice with HF will be evaluated. Furthermore, the contribution of Nek6 in epigenetic alterations in hippocampal microglia and memory dysfunction in mice with HF will be discerned (Aim 1.2).