Dementia

Tau

What are tauopathies?

The microtubule binding protein, tau, is one of the primary proteins that become dysfunctional in certain dementias. These diseases, collectively known as “tauopathies”, include Alzheimer’s disease, frontotemporal dementia, and others. In disease, tau becomes dysregulated and accumulates within the brain to form neurofibrillary tangles, leading to both neuronal degeneration and behavioral abnormalities. Thus, tau has become an important target for the development of therapies that can prevent, halt, or reverse dementia.

Can tau be targeted by drug intervention?

The Miller Lab is currently investigating the therapeutic ability of antisense oligonucleotides (ASOs) to target tau in dementias. ASOs are small DNA-like molecules that are able to prevent the production of a protein or modify its structure, enabling us to either lower tau or reduce tau’s disease-causing properties. Through the use of various genetic mouse models of dementia, we are currently testing ASOs designed to reduce tau protein within the brain as a way to prevent or even reverse tau pathology. Based on our work in ALS, we have demonstrated that ASOs can be both safe and effective when delivered to human patients. Our goal is to bring this novel therapeutic strategy to humans with tauopathies.

What is the Miller Lab currently doing in tauopathy research?

We are employing a variety of techniques, including histology, functional assessments, and small animal imaging, to understand the biological significance of tau and to identify potential therapeutic targets for Alzheimer’s disease and other tau-related dementias. We have previously shown that knocking down tau protein in healthy adult mice can lessen seizure severity, suggesting tau plays an important role in modulating neuronal hyperexcitability (DeVos et al., 2013). Our most recent data in a mouse model of tauopathy indicates tau reduction can reverse mutated tau pathology, lessen hippocampal volume loss, prevent functional deficits, and prolong survival in rodents and non-human primate models of tauopathy (DeVos et al., 2017). In addition, the Miller Lab is investigating tau isoforms (different structures of the tau protein) and their ability to be manipulated by ASOs for therapeutic benefit. We recently showed that the “4R” form of tau is toxic in rodent models, suggesting that targeting 4R tau may be one potential therapeutic method. By using a different kind of ASO that changes 4R tau to the less toxic 3R tau form, we provided the very first evidence that this 4R tau-targeting ASO was effective in rodent models (Schoch et al., 2016).

 
For more information on our tau-related projects in dementia, please contact us.

 

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