Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Neurosciences

Language

English (en)

Date of Award

Summer 9-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Timothy M Miller

Abstract

The protein tau is a major contributor in some of the most prevalent neurodegenerative diseases, including the most common form of dementia, Alzheimer's Disease (AD). As a member of the microtubule-associated protein family, tau in enriched in the axons of mature and growing neurons, though under certain conditions, can become hyperphosphorylated and accumulate into toxic oligomeric species and aggregates. In the studies outlined here, we sought to directly target the protein tau using Antisense Oligonucleotides (ASOs) to reduce total expression of tau in vivo and assess if such a reduction could be therapeutically beneficial. To first test the feasibility of reducing tau in the adult animal, we identified ASOs that reduce endogenous mouse tau in the brain and found no effect on baseline motor or cognitive behavior. We then tested the efficacy of reducing murine tau in the context of hyperexcitability since aberrant neuronal excitability has been linked to AD pathogenesis, both in humans and in amyloid-beta depositing mouse models. We found that mice with reduced tau had significantly less severe seizures than control mice, demonstrating that endogenous tau is indeed integral for regulating neuronal hyperexcitability. While the inducible models are sufficient to assess the roles of endogenous tau, non-transgenic mice do not develop tau aggregates. One of the main pathological AD hallmarks is the presence of tau inclusions, so to better test the effect of tau reduction on pathological tau species, we reduced human tau in a transgenic tauopathy mouse model that develops extensive tau pathology. Following treatment with a human tau ASO, not only did reducing human tau prevent additional tau aggregates from forming, it also allowed for a striking reversal of tau accumulations and hippocampal neuronal loss in aged tauopathy mice. Taken together, the safety of reducing endogenous tau in adult animals, the protective effect against neuronal hyperexcitability, and the ability to clear pre-existing tau aggregates, a tau lowering therapy using ASOs may be a viable and strong therapeutic approach for those human patients with a detrimental hyperexcitability profile, tau inclusions, or even both.

DOI

https://doi.org/10.7936/K77M05Z7

Comments

This work is not available online per the author’s request. For access information, please contact digital@wumail.wustl.edu or visit http://digital.wustl.edu/publish/etd-search.html.

Permanent URL: http://dx.doi.org/10.7936/K77M05Z7

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