Studying the Interactions Between Tau, Amyloid, and α-Synuclein in Alzheimer’s Disease Animal and Human Cell Models
- Author(s): Chen, Wesley
- Advisor(s): Blurton-Jones, Mathew
- et al.
Alzheimer’s disease (AD) is the leading cause of age related dementia and involves a progressive loss of neurons and synapses, leading to anxiety, cognitive impairment and a diminished quality of life. Pathologically, AD is characterized by extracellular amyloid beta (Aβ) plaque accumulation and the intraneuronal formation of tau-laden neurofibrillary tangles. In up to 70% of AD patients, these two hallmark pathologies are accompanied by a third proteinopathy; the aggregation of α−synuclein into intraneuronal Lewy bodies. The aggregate stress caused by these proteinopathies interacts with the immune system to produce a chronic neuroinflammatory condition that can further exacerbate disease progression.
The goal of my dissertation is investigate how β-amyloid, tau and α-synuclein pathologies interact with each other and to examine the role of the immune system in these interactions. To study how these proteinapathies interact in later stages of AD, I developed a new mouse model of AD termed ‘T5x’ mice, by crossing two existing transgenic lines; 5xFAD and Tau22 mice—aggressive lines that exhibit robust amyloidosis and tauopathy respectively. During my studies I found that T5x mice exhibit dramatically increased tau hyperphosphorylation, neuroinflammatory response, and microgliosis. However, quite surprisingly I also found that T5x mice exhibit increased microglial Aβ phagocytosis leading to decreased amyloid plaque burden and insoluble Aβ. In subsequent studies I further determine that T5x mice also develop inclusions composed of murine α-synuclein (α-syn) and form Lewy-body like pathologies—the first transgenic AD model to our knowledge to be found to develop Lewy body-like inclusions without an α-synuclein transgene.
To further study the specific effects that the immune system has on the development of tau pathology, I also developed a mouse model of tau pathology lacking the adaptive immune. Thy1-Tau22 mice were crossed with Rag2-/-/Il2rγ-/- double knockout mice over multiple generations to create ‘RagTau’ mice. RagTau mice lack T-, B- and NK-cells, yet exhibit significant accumulation and hyperphosphorylation of human tau. Although RagTau mice exhibit increases microglial activation relative to immune-intact Tau22 transgenics, no significant increases in tau pathology were detected in RagTau mice. To further validate the minimal influence of the adaptive immune system on the development of tau pathology, I performed adoptive transfer experiments, transplanting bone marrow cells from strain-matched GFP donors into RagTau mice. Using this approach I examined the potential effects of bone marrow reconstitution on tau pathology and the infiltration of GFP-labeled cells into the brain of tau mice. Unlike recent equivalent studies performed in our lab with Aβ-producing mice, I detected no changes in tau pathology in response to bone marrow transplantation. However, I did find that tau pathology induces a significant increase in T-cell infiltration into the brain parenchyma in comparison to Rag-wild type recipients. Lastly, I was the first in our lab to establish the paradigm of generating human induced pluripotent stem cells (iPSCs). Using this approach I differentiated iPSCs into neural stem cells (NSCs) and transplanted into RagTau mice to examine potential questions about tau propagation. Interestingly, while iPSC-derived NSCs survived for at least 3 months post-transplantation I found no evidence that tau pathology could spread to these transplanted human cells. Taken together, my thesis research has helped to improve our understanding of the interactions between AD pathologies and the immune system.