Award Date

May 2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdisciplinary Programs

First Committee Member

Jefferson Kinney

Second Committee Member

Jeffrey Cummings

Third Committee Member

James Hyman

Fourth Committee Member

Samantha John

Fifth Committee Member

Chad Cross

Number of Pages

228

Abstract

Alzheimer’s disease (AD) is an irreversible and devastating neurodegenerative disease characterized by progressive synaptic, dendritic, glial, and neuronal loss, collectively leading to impairments in learning, memory, and deterioration of cognitive and behavioral functions. AD is the most common form of dementia accounting for 60-80% of all cases. AD affects approximately 7 million Americans and is the 6th leading cause of death in the US. Furthermore, by 2050, the US is projected to spend over $1.1 trillion on AD-related treatments. Pathological hallmarks of AD include beta-amyloid (Aβ) plaques, intracellular neurofibrillary tangles (NFTs), and chronic neuroinflammation, which can promote and exacerbate both Aβ and NFTs levels and lead to synaptic and neuronal loss. AD is classified as either early onset (EOAD) or late onset (LOAD). EOAD is associated with genetic mutations and accounts for 3-5% of all AD cases. In contrast, LOAD accounts for 95-97% of all AD cases with no genetic etiology; however, several genetic and/or other comorbidities confer increased risk for LOAD. Diabetes mellitus (DM) is a major risk factor for AD. DM confers up to a 4-fold increased risk for developing AD, and approximately 81% of individuals with AD have type II diabetes (T2DM) or are glucose intolerant. Hyperglycemia – abnormal elevated blood glucose levels – is the primary characteristic of DM. We have previously shown that chronic hyperglycemia can initiate and promote neuroinflammation, resulting in significant increases in hyperphosphorylated tau protein (pTau), learning and memory impairments, and other AD-related targets that are consistent with other AD models. However, the mechanisms by which chronic hyperglycemia increases Aβ levels are still being elucidated. We administered low and staggered dosages of streptozotocin (STZ), a diabetogenic drug that selectively targets and destroys insulin producing β-cells, to induce hyperglycemia in a well-established male mouse model of human Aβ progression ( APP/PS1). The project aim was to investigate the underlying mechanisms by which chronic hyperglycemia increases Aβ levels. Briefly, our data indicate altered fasting blood glucose levels (BGLs), dysfunctional metabolic metrics, behavioral learning and memory deficits, increased Aβ load, and AD- and DM-related protein targets in the hippocampus, a region that is first affected by AD. These findings provide critical insight into the molecular pathways by which DM exacerbates AD pathogenesis, which may guide the development and/or amelioration of novel therapeutic strategies for individuals affected by both DM and/or AD.

Disciplines

Cell Biology | Medical Neurobiology | Molecular Biology | Neuroscience and Neurobiology | Neurosciences

Degree Grantor

University of Nevada, Las Vegas

Language

English

Rights

IN COPYRIGHT. For more information about this rights statement, please visit http://rightsstatements.org/vocab/InC/1.0/

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