Changing the “flavor” of tau: Application to mouse models of neurodegenerative disease
Washington University in St. Louis
Advisor: Dr. Eugene Johnson
Supervisor: Dr. Tim Miller
Neurodegenerative diseases, collectively known as tauopathies, are characterized by abnormal accumulations of the protein tau. The most well-known and widely studied tauopathy is Alzheimer’s Disease. Although the underlying causes and progression of these devastating diseases are under considerable investigation, the deposition of tau suggests it is a main contributor to disease and, therefore, is a primary target of interest for the development of effective therapies.
My research within the Miller laboratory in association with the Washington University Knight Alzheimer’s Disease Research Center will focus on reduction of the tau protein in models of tauopathy and Alzheimer’s disease in order to investigate tau’s role in disease progression and to screen potential therapeutics for disease intervention. I plan to use small DNA sequences known as antisense oligonucleotides (ASOs) that target the tau gene resulting in either a decrease in tau or manipulations to the tau protein that may potentially lessen tau-mediated pathology and behavioral deficits. These results will be essential in implicating tau as a central disease mediator and key target for the treatment of tauopathies and Alzheimer’s disease. Upon completion of these studies, we will have determined the influence of tau on age-related tau pathology and cognition in models of human neurodegeneration. These studies also may lend critical support for ASOs as a promising, novel therapy for tauopathies.
A hallmark feature of Alzheimer’s disease and other dementias is the abnormal deposition of the protein tau. Tau is present in all humans in several structurally different forms based on the number of repeat regions it contains. These forms can be grouped into those having three repeat domains (3R) or those with four domains (4R). In disease, tau functions abnormally and begins to accumulate within the brain leading to problems with movement, changes in personality, and memory loss. Interestingly, certain dementias can be caused by mutations in tau that lead to exclusive 4R tau expression and can show preferential accumulation of 3R or 4R tau within the brain. Therefore, strategies aimed at reducing or manipulating tau to lessen disease symptoms or halt disease progression are being extensively researched.
To better understand 3R and 4R tau in disease, we asked 1) whether reducing 4R tau will lessen tau accumulation and behavioral deficits observed in a mouse model of tau-related disease and 2) if driving greater 4R tau expression would worsen disease outcome. To manipulate tau in our mouse models, small DNA sequences known as antisense oligonucleotides (ASOs) were used to either decrease 4R tau or increase 4R tau expression. Our results indicate that switching tau from the 4R to 3R form improved movement, restored normal behavior, and lessened tau accumulation in our mouse model. When ASOs were used to increase 4R tau, mice exhibited more severe seizure behavior and greater pathological tau burden in the brain, suggesting greater 4R exacerbates disease. These data implicate 4R tau as a primary mediator of behavioral deficits and brain pathology evident in tau-related dementias. Furthermore, these data support tau manipulation by ASO to specifically target 4R tau as an effective therapy for select neurodegenerative diseases.