Watch Dr Pablo Miguel Casillas-Espinosa accept his research grant and hear a bit about the project.
Project Summary:
Ischemic stroke is a common neurological condition that often results in debilitating lifelong consequences. One of the most severe, yet understudied consequence of stroke is the development of post-stroke epilepsy. Unfortunately, there is currently no intervention known to prevent the long-term neurological consequences of stroke.
Tau is a protein that plays a critical role in the normal function of the neurons. Tau undergoes phosphorylation and dephosphorylation changes that are tightly regulated by Protein phosphatase 2A (PP2A).
However, we have shown that in a number of neurodegenerative diseases, like traumatic brain injury, Alzheimer’s, Parkinson’s and epilepsy, PP2A dysfunction and tau its hyperphosphorylated. This hyperphosphorylation of tau creates aggregates of the protein which destabilise the structure and function of the neurons, promoting the development of brain diseases.
However, we have previously show that treatment with sodium selenate, which is a drug that improves the function of PP2A, helps to decrease the hyperphosphorylation of tau, to improve memory and mobility, but also prevents the development of epilepsy after traumatic brain injury.
We now have exciting preliminary data showing that tau is hyperphosphorylated and PP2A dysfunctions in a model of ischemic stroke. Based on these promising results, this project will now test the hypotheses that hyperphosphorylated tau and PP2A contribute to the brain damage and consequences of stroke. We will also evaluate if treatment with sodium selenate can prevent the brain damage, mobility impairments, chronic pain, anxiety, social dysfunction, depression, learning and memory deficits and epilepsy after stroke.
Sodium selenate treatment is already in clinical trials in other neurological conditions, thus this project has the strong potential to impact the medical management of stroke patients in the foreseeable future.
Outcomes:
The Brain Foundation research gift allowed us to investigate tau as potential biomarker and treatment target to improve outcomes after ischemic stroke.
We conducted positron emission tomography (PET) imaging using a world-first, novel Tau tracer to examine the expression of the Tau protein in a rat model of stroke. We found that tau is increased in brain areas known as the striatum and adjacent cortical regions, as early as 1 day after ischemic stroke. This work provides important proof of concept for the utility of this tracer to study the role of Tau in stroke. Similarly, we showed that tau and htau protein expression is increased, PP2A expression is decreased in the same brain regions and in peripheral blood. Moreover, tau-PET and tau protein changes correlate with motor problems that present after ischemic stroke.
Our findings show that tau protein and brain imaging biomarkers may be means to identify pathological changes after stroke and to guide patient-specific interventions. Furthermore, our findings highlight tau as a potential treatment target to prevent motor problems that occur after stroke. We will next test the effects of the anti-tau drug, sodium selenate, to investigate if by pharmacologically targeting tau we can prevent stroke-related deficits and improve outcomes after ischemic stroke.
We thank the Brain foundation and its donors for the support to science and to our research.
Outcomes submitted May 2021.
The Brain Foundation is dedicated to funding the next generation of Australian research into brain disorders, diseases, and injuries, with the ultimate goal of advancing diagnoses, treatments, and patient outcomes.