Targeting Tau with Immunotherapy in a Mouse Model of Alzheimer's Disease: A Comparison of Approaches

Yona Levites, PhD
University of Florida (Gainesville, FL)
Year Awarded:
2014
Grant Duration:
July 1, 2014 to June 30, 2017
Disease:
Alzheimer's
Award Amount:
$248,009
Grant Reference ID:
A2014105S
Award Type:
Standard
Award Region:
US Southeastern
This grant is made possible by a bequest from the estate of Virginia Eberwein.

Tau, Aβ and Network Degeneration in Alzheimer’s Disease

Summary

Tau protein is known to go through abnormal changes that cause it to accumulate in the brains of Alzheimer’s patients for yet unclear reasons. Immunotherapy using recombinant molecules (ie, molecules formed in the laboratory through genetic recombination) has emerged as a promising approach to target tau accumulation; however, many questions persist about the optimal form of anti-tau immunotherapy. We propose to compare the ability of genetically engineered antibodies targeted to the intracellular or extracellular levels to fight tau pathology in two mouse models.

Our results will provide critical insights into which method is more effective (ie, extracellular vs. intracellular) and whether the full-length antibody and not just its binding fragment is required.

Details

Tau protein is known to go through phosphorylation and to accumulate in the brains of Alzheimer’s patients where, in this altered form, it contributes to neuronal dysfunction and death. Phosphorylation turns many protein enzymes on and off, thereby altering their function and activity, and this plays a significant role in a wide range of cellular processes. Anti-tau immunotherapy has emerged as a promising approach to target this pathological conversion, but many questions regarding the optimal form of anti-tau immunotherapy remain open.

In our search for potential modifiers of Alzheimer’s disease (AD) pathology in mouse models, we have developed a “somatic brain transgenics” paradigm, consisting of genes packaged into adeno-associated viral vectors and delivered to the brains of newborn mice by injection.

We propose to compare the ability of recombinant intracellular and extracellular antibodies to attenuate tau pathology in two mouse models.

Results from these studies will provide critical insights into a) whether targeting tau in the extracellular vs. intracellular compartment is more efficacious and, b) whether full length antibody and not just its binding fragment antibody effector functions are required.

About the Researcher

Yona Levites received her PhD under the supervision of Professor Moussa Youdim from the Technion, Israel, in whose laboratory she worked. Her graduate work concentrated on effects of green tea on prevention of Parkinson’s and Alzheimer’s diseases. She completed her postdoctoral training at the Mayo Clinic College of Medicine, (WHERE), where she worked on developing immunotherapy strategies for Alzheimer’s disease. Dr. Levites is an assistant professor at the University of Florida Center for Translational Research and Neurodegenerative Disorders.