Advisor(s)
Ashley Harms
Committee Member(s)
Briana De Miranda
David Standaert
Jeremy Herskowitz
Laurie Harrington
Document Type
Dissertation
Date of Award
6-1-2026
Degree Name
Doctor of Philosophy (PhD)
School
Joint Health Sciences (Interdisciplinary)
Department
Neurobiology
Abstract
Neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson disease (PD) often present with overlapping proteinopathies rather than aggregated proteins in isolation. Amyloid-β (Aβ) and phosphorylated tau are found in a substantial proportion of idiopathic PD cases, while α-synuclein (α-syn) pathology is present in over half of AD cases. The presence of these co-pathologies is associated with accelerated cognitive decline and increase mortality in these patients. In parallel, neurodegenerative diseases are increasingly recognized as being shaped by interactions between central nervous system (CNS) pathology and the immune system. Despite this, most experimental animal models of neurodegenerative disease examine single pathologies in isolation, leaving how the question of how co-pathologies interact to drive neuroinflammation and neurodegeneration unanswered. To address this gap, we developed a novel mouse model incorporating tau, Aβ and α-syn as co-pathologies. Using this model, we show that co-pathologies synergistically prompt a distinct and amplified neuroinflammatory response compared to single pathology conditions. This response is characterized by robust expansion of CD4+ and CD8+ tissue-resident memory T cells and accumulation of CD68+ activated microglia within the hippocampus and cortex. These immune changes coincide with increased protein pathology burden at 3 and 6 months post-induction and enhanced hippocampal neuron loss at 6 months post-induction, suggesting a strong association between co-pathology-driven neuroinflammation and neurodegeneration. Building on these findings, we examined the contribution of peripheral adaptive immune cell trafficking to neuroinflammation and disease progression in the context of co-pathologies. While innate immune activation and antigen presentation by microglia are hallmarks of neurodegeneration, the role of leukocyte trafficking in the CNS remains incompletely defined in the context of co-pathologies. Consistent with prior work, blockade of integrin VLA-4 altered immune cell populations in the brain, including microglia and significantly increased tau, Aβ and a-syn pathology burden. Τhese findings identify peripheral immune trafficking as potential protective in modulating protein pathology in co-pathology environment. By demonstrating that co-pathologies synergistically amplify neuroinflammation and neurodegeneration, this work highlights a fundamental limitation of single-pathology therapeutic approaches. Effective neurodegenerative disease modification may require combinatorial strategies that concurrently target overlapping proteinopathies and neuroinflammatory mechanisms.
Keywords
alpha syunclein;amyloid beta;microglia;neurodegenerative disease;T cells;tau
ProQuest ID
Recommended Citation
Webster, Jhodi Mickayla, "Neuroinflammation And Neuropathology In A Novel Tau, Amyloid-Beta And Alpha-Synuclein Co-Pathology Model" (2026). ETDs from 2020-2029. 159.
https://digitalcommons.library.uab.edu/etd-2020s/159
