Cyclin-Dependent Kinase Inhibitors and Neurodegenerative Tauopathy

Increased levels of cellular senescence have been linked to neurodegenerative tauopathies for decades. As such, researchers are keenly focused on senescent cells as viable therapeutic targets for these diseases. While senescent cells are highly associated with tauopathies like Alzheimer’s disease, thorough characterization and understanding of the mechanism(s) by which senescent cells contribute to disease are lacking. The work in this thesis aims to establish p16high and p21high senescent cells as drivers of tau-mediated neurodegenerative disease and present a working model for underlying mechanisms that can be tested in future studies.
Chapters 1-4 outline the current state of cellular senescence research, as well as the utility of mouse models to study the interplay between senescent cells and neurodegeneration. Chapters 5 and 6 establish p16 and p21 expression as requirements for normal disease progression in a mouse model of tauopathy. Particularly, p16 expression in microglia and endothelial cells is necessary for disease, regardless of sex. Interestingly, loss of p21 is beneficial in female, but not male, tauopathy mice. Chapter 7 describes several new model systems in which to test the role of p16 or p21 expression in different brain cell types during disease. Chapter 8 looks at how different types of stress impact certain aspects of tauopathy in mice. Finally, Chapter 9 provides a proposed model for how p16high and p21high cells may drive neurodegenerative tauopathy through inflammation and blood brain barrier breakdown.