Dissertation
Rethinking the relationship between tau and Alzheimer’s disease with insights from the developing brain
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2023
DOI: 10.25820/etd.007080
Abstract
The clinicopathologic, pathobiological, and vernacular definitions of Alzheimer's disease (AD) have struggled to classify this disease for over a century, and we still lack an etiologically-cohesive definition of AD. Early histopathology established the foundation of the “trigger and bullet model” for amyloid-beta and tau, which has dominated and misled the field for decades. The consistent failure of amyloid-beta-targeting drugs reflects the narrow clinicopathological view of AD from which they originate, as we now understand the primary driver of neurodegeneration to be soluble, mislocalized tau. This thesis presents a discussion of the theories driving past and present AD research alongside new evidence for a selective failure of proteostasis specific to the aging brain.
It was long theorized that hyperphosphorylated tau was inherently cytotoxic and always a precedent of disease, but we show that such tau exists in the human brain throughout much of neurodevelopment. Despite similarities in phosphorylation, the localization and binding profile of tau differs greatly between the adult and fetal brain. We used histological, proteomic, and biochemical techniques to better characterize one aspect of this diverged behavior: interaction with 14-3-3-beta. We determined that tau/14-3-3-beta interaction is absent in the fetal brain, highly enriched in AD, and requires both tau phosphorylation and inclusion of the 2nd microtubule binding domain repeat. The latter of which is only seen in the mature brain, providing a regulatory mechanism by which this interaction may be upregulated in AD to drive pathological processes.
Details
- Title: Subtitle
- Rethinking the relationship between tau and Alzheimer’s disease with insights from the developing brain
- Creators
- Ryan Kenly Betters
- Contributors
- Marco M. Hefti (Advisor)Michael E. Dailey (Committee Member)Lilliana Radoshevich (Committee Member)Catherine Marcinkiewcz (Committee Member)Stefan Strack (Committee Member)Joshua Weiner (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Neuroscience
- Date degree season
- Summer 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007080
- Number of pages
- xi, 95 pages
- Copyright
- Copyright 2023 Ryan Kenly Betters
- Language
- English
- Date submitted
- 06/06/2023
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 76-95).
- Public Abstract (ETD)
Alzheimer’s disease (AD) is the leading cause of disability in older individuals and its prevalence has more than doubled in the last thirty years. An aging world population and global shifts of disease burden is accelerating this change far beyond our healthcare system’s capabilities. The increase in prevalence is compounded by the apparent lack of actionable risk factors and the consistent failure of clinical trials to yield disease-modifying treatments. Recent studies found striking similarities between the regulation of tau in AD and during normal brain development, but it is not yet understood why the fetal brain does not undergo the pathological changes seen in AD. We present evidence that the type of tau found in the fetal brain may play a role, as it is distinct from tau in the adult brain and demonstrates unique binding activity to disease-relevant proteins. We analyzed tau binding activity to better understand how it behaves in different physiological conditions and inform us as to how these proteins might drive relevant disease processes.
Based on its prevalence in the AD brain and known involvement in cell death and neurodegenerative disease, we chose to characterize 14-3-3-beta by investigating the molecular requirements of its interaction with tau. We found that age-related shifts in tau regulation are necessary for this interaction, showing an avenue by which selective failures of protein regulation may contribute to disease. More work needs to be done to determine if tau/14-3-3-beta interaction acts through expected pathways such as programmed cell death and protein transport, or through novel, unanticipated mechanisms. The identification of beta-amyloid-independent drivers for AD is critical for a field that otherwise lacks research diversity; this previously undescribed interaction has potential implications for the role of tau in AD and could open new avenues for both basic and translational research.
- Academic Unit
- Interdisciplinary Graduate Program in Neuroscience
- Record Identifier
- 9984454319802771
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