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

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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).