Defense Date
2026
Document Type
Thesis
Degree Name
Master of Science
Department
Biochemistry
First Advisor
Carmen Sato-Bigbee
Abstract
Our laboratory previously found that the endogenous peptide Nociceptin blocks the premature differentiation of oligodendrocytes (OLGs) into mature myelin-making cells, a mechanism that prevents untimely precocious myelination in the developing brain. Supporting this regulatory function, Nociceptin levels are developmentally controlled, sharply decreasing with the initiation and progression of myelination, suggesting that later pathological increases may contribute to impairments in myelin regeneration and/or maintenance in the mature brain. In this regard, we have recently found that Nociceptin synthesis is increased in human astrocytes when exposed to microglial pro-inflammatory cytokines known to be elevated in the most severe forms of multiple sclerosis (MS), and studies in aged mice strongly suggest that this peptide plays a crucial role in the age-dependent progression of this disease. Those observations led us to examine Nociceptin levels in the cerebrospinal fluid (CSF) of patients with Alzheimer’s Disease (AD) and related dementias (RD) as demyelination is also observed in these age-dependent pathologies with local microglial activation and astrocyte reactivity. Comparison with healthy age-matched controls indeed indicated significantly increased levels of Nociceptin in the CSF of these patients, posing the question of whether Nociceptin could be contributing to the pathology of AD and RD through dysregulation of OLGs' remyelinating and/or myelin maintenance properties. To further investigate this problem, first we assessed myelination by immunohistochemical detection of myelin basic protein (MBP) in different brain areas - including corpus callosum, cingulate cortex, and hippocampus - of control individuals and AD/RD patients. Subsequent immunohistochemistry revealed the expression of the Nociceptin receptor (NOR) across the oligodendroglial lineage including NG2+ OLG progenitor cells (OPCs) and myelinating MYRF+OLGs, pointing to roles of Nociceptin signaling at different stages of OLG development. In support of this possibility, RNA sequencing of cultured OPCs treated with Nociceptin indicated upregulation of proliferation-related genes but downregulation of differentiation-related genes. Findings of these studies suggest that increased Nociceptin levels in AD/RD patients may play an important role in the observed myelin deficits by inhibiting the ability of OPCs to generate mature OLGs capable of myelin maintenance/repair. As a member of the G-protein coupled receptor superfamily, NOR may offer a unique target for pharmacological intervention to prevent myelin deficits linked to cognitive decline in both physiological brain aging and Alzheimer’s disease.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
6-19-2026