Will modulating Tau improve behavioral phenotype and what is the role of different tau isoforms?
The microtubule binding protein tau has been widely implicated in the pathogenesis of Alzheimer’s disease, frontotemporal dementia, and other neurodegenerative diseases, collectively known as tauopathies. The neurofibrillary tangles formed by the abnormal hyperphosphorylation and deposition of tau suggests a tau-mediated mechanism of disease and, therefore, is a primary target of interest for the development of effective therapies. We have developed an antisense oligonucleotide strategy to decrease levels of tau or change tau splicing in mouse models of tauopathy enabling us to 1) determine the biological significance of tau and different tau isoforms and 2) identify potential therapeutic targets for Alzheimer’s disease and other tau-mediated dementias.
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. Under normal conditions, tau binds to microtubules of neurons for stability and structural support. However, in disease, tau becomes dysregulated and accumulates within the brain (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.
1. How can tau be modulated 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 pathological properties. Through the use of various genetic mouse models of dementia, we are comprehensively testing the dosage, duration, and efficacy of tau-targeted ASOs toward the development of new therapeutic interventions for human clinical trials.
Based on our work in ALS, we believe ASOs can be both safe and effective when delivered to human patients.
2. Will modulating tau improve behavioral phenotype?
Tau dysregulation and accumulation are hallmarks of several dementias, including Alzheimer’s disease. We are currently testing ASOs designed to reduce tau protein within the brain as a way to prevent or even reverse tau pathology. We are employing a variety of techniques, including histology, functional assessments, and small animal imaging, to understand the progression of tau toxicity and its modulation by tau knockdown ASOs.
We have previously shown that tau knockdown 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 phosphorylated tau pathology, attenuate hippocampal volume loss, prevent functional deficits and prolong survival.
3. What is the role of different tau isoforms?
Tau is found within the brain in several different isoforms that differ based on their structure and regulation throughout development. Although tau isoforms are not reported to have different physiological functions, certain tau isoforms selectively deposit within neurofibrillary tangles of tauopathies and Alzheimer’s disease. Furthermore, certain dementias can be caused by genetic mutations that affect tau isoform expression.
The Miller Lab is currently investigating whether the 4-repeat, or 4R, tau isoform partially mediates tau toxicity in dementia. Using ASOs that alter tau isoform composition without changing total tau levels within the brain, we are assessing both functional and pathological outcomes following tau isoform manipulation. Our lab is the first to test ASOs that alter specific tau isoforms in animal models in an effort to identify novel tau targets for disease intervention.
For more information on our tau-related projects in dementia, please contact us.