Dissertation
Drivers of astrocytic tau pathology in 4R tauopathies
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007102
Abstract
Toxicity caused by abnormal accumulations of tau protein is the final step in the pathway of many neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD-tau), chronic traumatic encephalopathy (CTE), and other tauopathies. Though this process has been extensively studied in neurons in the context of AD, the mechanisms that drive this same process in astrocytes, and how that in turn drives diseases like FTLD-tau, remain poorly understood.
Using a combination of human tissue and human embryonic stem cell-derived (hESC) astrocytes, we sought to uncover the origin of astrocytic tau in FTLD-tau and the potential candidate mediators of tau accumulation in astrocytes in vitro. We used RNA in situ hybridization and immunofluorescence on cases of AD, PSP, and CBD to compare total amounts of tau mRNA between diseases and between astrocytes with and without tau pathology in PSP. We then used hESC-derived astrocytes to assess their ability to take up and degrade different isoforms of tau.
We saw no significant differences in astrocytic tau mRNA expression between diseases with and without astrocytic tau pathology or between individual astrocytes with and without pathology in our PSP cohort. We also found that both control and reactive astrocytes in vitro preferentially take up 4R tau, but only reactive astrocytes exhibit significantly impaired uptake and degradation. Across diseases, astrocytes with tau pathology do not show elevated markers associated with the neurotoxic A1 reactive astrocyte phenotype.
Taken together, this data suggests that neuronal and astrocytic tau in FTLD-tau shares a common neuronal origin, and that the preferential uptake and subsequent impaired degradation of 4R tau may explain why 4R accumulation is more common in astrocytes. These results also suggest that tau uptake by astrocytes may have a protective function. Future work focused on characterization of the neuroprotective A2 reactive astrocyte phenotype, in addition to an in-depth exploration of the candidate mediators of tau uptake and degradation, is necessary to further understand the role of astrocytes in FTLD-tau.
Details
- Title: Subtitle
- Drivers of astrocytic tau pathology in 4R tauopathies
- Creators
- Kimberly Lynn Fiock
- Contributors
- Marco Hefti (Advisor)Munir Tanas (Committee Member)Catherine Marcinkiewcz (Committee Member)Georgina Aldridge (Committee Member)Jia Luo (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Experimental Pathology)
- Date degree season
- Spring 2023
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.007102
- Number of pages
- xxi, 130 pages
- Copyright
- Copyright 2023 Kimberly Lynn Fiock
- Comment
This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/.
- Language
- English
- Date submitted
- 04/10/2023
- Date approved
- 04/24/2023
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 113-122).
- Public Abstract (ETD)
- Although best known for its role in Alzheimer’s disease (AD), the tau protein is involved in the development of multiple neurodegenerative diseases called tauopathies, including the lesser-known frontotemporal lobar degeneration with tau (FTLD-tau). What makes AD and FTLD-tau different, however, are the types of cells affected by tau pathology. Astrocytes are helper cells that support neurons by providing nutrients, recycling garbage, and protecting the brain from injury. When a disease process is underway, astrocytes become reactive, which changes the way they interact with their environment and the cells around them. Research supports the role of reactive astrocytes in disease progression, but little work has been done on their role specifically in diseases with astrocytic pathology. We therefore sought to identify how astrocytes accumulate tau pathology in FTLD-tau and whether reactivity contributes to this. Using human tissue and human-derived astrocytes, we assessed the amount of available template that astrocytes use to produce tau protein and found that cells with and without pathology do not have differing levels. We also found that astrocytes likely take up tau from their environment in order to degrade, or get rid of, it, but they take up certain forms of tau better than others. We then showed that reactive astrocytes take up tau less efficiently than normal astrocytes and have difficulty degrading it once they do. This may explain why only this type of tau is found in astrocytes in FTLD-tau and helps us better understand the mechanisms that lead to the development of this disease.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984428942502771
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