TREM1-Mediated Neuroinflammation is Critical to Global Ischemia-Induced Neurodegeneration and Cognitive Deficits.
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Authors
Urquhart, Rachael
Issue Date
2024
Volume
Issue
Type
Thesis
Language
en_US
Keywords
GLOBAL ISCHEMIA , HIPPOCAMPUS , NEUROINFLAMMATION , STROKE , TREM1
Alternative Title
Abstract
Global cerebral ischemia occurs when blood flow to the entire brain is significantly reduced; this occurs most commonly following cardiac arrest. Following global ischemia, there is delayed and selective loss of neurons in the hippocampal CA1, a critical brain region for learning and memory, ultimately leading to cognitive impairments. While therapies for cardiac arrest primarily focus on restoring blood flow and cardiac function, there are currently no effective treatments that address the global ischemia-induced neurological deficits. Understanding the molecular mechanisms underlying the pathophysiology of global ischemia is therefore critical for identifying novel therapeutic targets and developing interventions to mitigate these devastating outcomes. Although the mechanisms underlying the global ischemia pathology are not yet fully understood, it is established that the significant delay between insult and neuronal death is consistent with a role for transcriptional changes. In this study, to determine how dysregulation of genes contributes to global ischemia pathology, we performed RNA sequencing on hippocampal CA1 from rats subjected to global ischemia via 4-vessel occlusion. RNA-seq and Ingenuity Pathway analysis determined that, following global ischemia, genes related to neuroinflammation, and the triggering receptor expressed on myeloid cells-1 (TREM1) signaling are significantly upregulated in the hippocampal CA1. TREM1 is a pivotal myeloid-derived immune cell surface receptor with known roles in systemic inflammatory conditions, including myocardial ischemia and sepsis. In recent years, TREM1 has been implicated in neurological conditions, suggesting a role for neuroinflammation in the pathology of neurological disorders and diseases. To date, there are no known studies that have explored the connection between TREM1-mediated neuroinflammation and global ischemia pathology.
Here we show global ischemia induces upregulation of TREM1 and related inflammatory cytokines and further increases microglial activation, astrogliosis, and loss of blood-brain barrier structure and function. In contrast, TREM1 inhibition via inhibitory decoy receptor peptide LR12, recuses these events indicating that TREM1 plays a critical role in global ischemia-induced neuroinflammation. Moreover, administration of LR12 decreases neurodegeneration and attenuates cognitive deficits associated with global ischemia. This is the first study to establish a causal relationship between TREM1-mediated neuroinflammation and global ischemia pathology, suggesting TREM1 as a potential therapeutic target for treating global ischemia-induced neurodegeneration and cognitive deficits.
In the first chapter of this dissertation, I provide an overview and background on global cerebral ischemia, neuroinflammation, and the TREM1 signaling pathway, and discuss recent studies related to these topics. In the second chapter, I present and interpret the data, analyses, and findings, followed by a discussion of the conclusions and potential directions for future research.
Description
2024
Citation
Publisher
Creighton University
License
Copyright is retained by the Author.
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