TREM1-Mediated Neuroinflammation Is Critical to Global Ischemia-Induced Neurodegeneration and Cognitive Deficits

 Even though this is for cardiac induced ischemia our competent? researchers should evaluate this for possible use in saving neurons post stroke. But that won't occur; THERE IS NO LEADERSHIP IN STROKE. Everything in stroke is a complete fucking failure!

TREM1-Mediated Neuroinflammation Is Critical to Global Ischemia-Induced Neurodegeneration and Cognitive Deficits

By

RACHAEL URQUHART

___________________________________

A DISSERTATION

Submitted to the faculty of the Graduate School of the Creighton University in

Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy in

the Department of Pharmacology and Neuroscience

________________________

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

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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.