Advisor(s)

Lori McMahon

Committee Member(s)

Ashley Harms
Jeremy Herskowitz
John Chatham
Michael Scofield

Document Type

Dissertation

Date of Award

6-1-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Neurobiology

Abstract

Alzheimer’s disease (AD) is currently the 7th leading cause of death, with few treatment options. It is known that AD pathology begins 20-30 years before clinical symptoms manifest. Some of the earliest pathological changes occur in glial cells of the hippocampus, causing them to become chronically reactive, as well as the accumulation of Amyloid-β (Aβ) in the hippocampus and hyperphosphorylated Tau (pTau) in the locus coeruleus, resulting in dysfunction of the noradrenergic (NA) system. Preclinical studies have shown promise in the abilities of the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a tightly regulated reversible enzymatic modification controlled by the enzymes O-GlcNAc transferase (OGT), which add or remove the O-GlcNAc moiety of β-N-acetylglucosamine to Ser/Thr residues on proteins, respectively. O-GlcNAc has the ability to compete with phosphorylation and reduce pTau in mouse models of AD and tauopathy models. In contrast, its ability to modulate the production of Aβ has been demonstrated in cell culture, and it is also influence inflammation. No study has examined how the chronic increase of O-GlcNAc in the early stages of AD affects glial cells, such as astrocytes and microglia, the loss of NA innervation into the dentate gyrus, or the accumulation of Aβ in the hippocampus. I tested this by cyclically increasing O-GlcNAcylation in TgF344-AD (Tg) rats after pathology has begun using Thiamet-G (TMG), an OGA inhibitor. Although I observed significant increases in in most pathological markers assessed TgF344-AD rats compared to WT rats, we see little effect of O-GlcNAc on pathology. We did observe a significant increase in astrocytic morphological characteristics in TgF344-AD rats treated with TMG (AD-T) compared to TgF344-AD saline controls (AD-S).

Keywords

Alzheimer's disease;Amyloid-β;Astrocytes;Microglia;Noradrenergic axons;O-GlcNAcylation

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