Graduation Year

2020

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Dave Morgan, Ph.D.

Co-Major Professor

Ross Andel, Ph.D.

Committee Member

Paula Bickford, Ph.D.

Committee Member

Alyssa Gamaldo, Ph.D.

Committee Member

Cathy McEvoy, Ph.D.

Committee Member

Brent Small, Ph.D.

Keywords

Alzheimer's disease, gerontology, neurobiology, neuroscience, tau

Abstract

Alzheimer’s disease (AD) is characterized by amyloid β plaques and neurofibrillary tau tangles (NFTs). While research has demonstrated amyloid pathology occurs prior to tau pathology, or tauopathy, tau has proven to be more toxic. Tauopathy is associated with cognitive declines and neurodegeneration. These findings have highlighted the importance of further understanding tauopathy. In the progression of tauopathy, there is an observable immune response that can be measured by glial cells such as microglia. Activated microglia are known to exacerbate tauopathy rather than reducing the pathology. Research has indicated that with increased age there is an increased risk for AD-related tauopathy and a more reactive, or primed immune response. Therefore, it is important to further understand how tauopathy and immune markers change in respect to age to potentially identify critical periods that might be advantageous for future interventions. This dissertation is aimed at understanding the effects of age and genetic mutant variants of tau in different animal models of tauopathy over three different studies.

In study one, a commonly used transgenic model of tauopathy, rTg4510, was studied to examine how markers of tauopathy and tauopathy-related pathology differ over the life course. Regression analyses were conducted to determine the best models of fit (linear vs non-linear models of fit) for each marker. Results indicated that not all the markers of pathology in this model progress at the same rate or in the same manner. However, there was an overall increase in pathological events with increased age; especially in histological sections and the detergent insoluble homogenate fraction that contains pathological aggregates.

In study two, age differences between young, middle-aged, and old animals that received either AAV9 GFP or AAV9 tauP301L intracranial injections were examined. Two-way ANOVAs and two-way repeated measures ANOVAs were conducted to determine group differences on measures of tauopathy, tauopathy-related markers of pathology including immune activation and neurodegeneration, and behavioral assessments of motor and cognitive impairments. These results indicated the old mice had higher levels of early phosphorylated tau, neurofibrillary tau tangles (NFTs), and reactive immune activation. Behavioral assessments evidenced a reduction in performance in the old animals irrespective of the injection group. However, only the younger GFP injected mice (young and middle-aged) were able to demonstrate mastery of the memory task. The old GFP and tauP301L injected mice were not able to achieve the historical learning criterion in the memory task.

In study three, viral constructs expressing different tau variants were employed including, AAV9 tauP301L, AAV9 tauR406W, AAV9 tauwild-type, and AAV9 GFP intracranial injections were conducted in middle-aged mice to identify whether tau mutations associated with human disease could produce a translational model of tauopathy. One-way ANOVAs and one-way repeated measures ANOVAs were conducted for measures of tauopathy, tauopathy-related pathology including immune activation and neurodegeneration, and behavioral assessments to determine any motor or cognitive deficits. The results indicated that both tauP301L and tauwild-type created models of tauopathy that include declines in a behavioral memory task. However, these two viruses displayed different mechanisms that warrant further investigation. TauP301L demonstrated the highest levels of insoluble tau and NFTs, similar to the rTg4510 model, while tauwild-type had the highest levels of histological phosphorylated tau, soluble tau, and exhibited the greatest amount of hippocampal atrophy.

This body of work demonstrates the importance of age in both transgenic and viral models of tauopathy. As demonstrated by studies one and two, there are changes that occur in animal models that can demonstrate a progression of pathology. This progression is critical as translational models of AD-related tauopathy are imperative for furthering the knowledge of tau and potential treatments. Additionally, the viral models validate the need to understand earlier events in the progression of pathology. The tauP301L and tauwild-type viruses both modeled tauopathy. However, these viruses, did so in distinct ways that warrant further investigation to determine if there are differences early in the progression of pathology that are driving the observed differences found in age and/or viral differences.

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