Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Dr. Kelly Stauch

Abstract

Alzheimer’s disease (AD) is the world’s leading cause of dementia, characterized by progressive atrophy of the hippocampal and cortical brain regions, synapse damage and loss, and a buildup of senile plaques and neurofibrillary tangles composed of β-amyloid peptides and hyperphosphorylated tau, respectively. While age is the most significant risk factor for developing AD, apolipoprotein E4 (APOE4) is the strongest genetic risk factor for AD. Although it is known that APOE4 influences tau pathology, the molecular mechanisms by which APOE4 drives AD pathogenesis and progression remain unclear. In addition to intrinsic contributions to AD, there are many extrinsic factors that can induce AD phenotypes. An example is traumatic brain injury (TBI) which can occur in many different aspects of life. In short, TBI is characterized by mechanical damage to the brain tissue followed by secondary events that further disturb important molecular processes later in recovery. A specific connection to AD is the induction of tau hyperphosphorylation at the site of injury following TBI. This modified tau can then aggregate and spread to adjacent brain regions, causing AD-relevant tau burden. Further, APOE4 carriers appear to experience worse outcomes after TBI. How TBI leads to subsequent AD development and the interrelationship between TBI and other AD-related contributors such as APOE4 and tau are areas of active investigation. The work in this thesis details the connections between APOE4 genetic risk, non-mutant human tau pathology, and TBI-induced secondary events and how they relate to the molecular underpinnings of AD pathogenesis and progression.

Comments

2025 Copyright, the authors

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