Repurposing Ebselen for TBI-Induced PSR Activation in Tauopathies and Alzheimer's Disease

Lay Abstract Each year, approximately 2.8 million Americans suffer from traumatic brain injuries (TBIs), resulting in tens of thousands of deaths and more than 200,000 hospitalizations, with many cases being treated and released from emergency rooms. Despite the immediate treatment of symptoms, long-term effects can still manifest later in life. Repeated TBIs lead to the accumulation of a harmful protein called tau, significantly increasing the risk of dementia and neurodegenerative diseases like Alzheimer''s disease (AD) and chronic traumatic encephalopathy (CTE). Although the connection between TBIs and abnormal tau formation is not fully understood, our research focuses on polyamines molecules which can support brain function under physiological conditions but can also worsen diseases through a chronic polyamine stress response (PSR). The PSR is thought to be protective under acute conditions but transitions to a detrimental state during sustained activation. We determined that PSR activation exacerbates tau dysfunction, with the protein spermidine/ spermine N acetyl transferase 1 (SSAT1) playing a crucial role in this process, leading to the accumulation of altered polyamines and tau aggregation. We propose that TBIs activate SSAT1, which increases the PSR, alters polyamine levels, and produces inactive metabolites that promote tau aggregation, worsening neurodegeneration. Our study aims to understand SSAT1’s role during this process and hypothesizes that the FDA-approved drug Ebselen can reduce tau-related brain damage by blocking PSR-SSAT1 activation. We plan to determine the appropriate dose of Ebselen to block the immediate PSR phase after repeated TBIs in a mouse model of tau and investigate how different doses, timings and durations of Ebselen treatment affect TBI-induced PSR activation, tau pathology, and cognitive deficits. Given the significant health concern posed by the long-term effects of TBIs and their strong association with Alzheimer''s disease, understanding these connections is crucial. Our research highlights the emerging polyamine stress response (PSR) triggered by both Alzheimer''s and TBIs and identifies SSAT1 as a key target for Ebselen treatment, potentially leading to immediate therapies for TBIs and their progression to Alzheimer''s disease.