Therapeutic Value of BNC-1 in Addressing Tau Pathology in TBI

PROJECT SUMMARY/ABSTRACT Each year, approximately 200,000 Americans aged 65 and older seek medical care for traumatic brain injuries (TBI), primarily from closed head injuries (CHI) from falls. Research shows that an individual suffering one TBI is at heightened risk for experiencing another. The ramifications extend beyond the immediate physical consequences: TBIs have been linked to an increased risk for all types of dementia, and repetitive TBIs have been correlated with the accumulation of hyperphosphorylated tau (p-tau), which is a defining feature of chronic traumatic encephalopathy (CTE). Our research and numerous other studies confirm the presence of elevated p-tau levels in the aftermath of a TBI. However, the precise mechanisms contributing to these changes are not fully understood. As we confront the complexities of these injuries and their long-term impact, it becomes crucial to identify the underlying mechanisms that promote these tau-related pathological changes. Doing so could pave the way for targeted therapeutic interventions following a TBI, reducing the risk of developing Alzheimer’s disease and related dementias. This study aims to examine the role of transforming growth factor-activated kinase 1 (TAK1) in tau pathology following a repetitive mild TBI in a humanized MAPT KI mouse model with the P301L risk variant of neuronal tauopathy. We found activated (phosphorylated) TAK1 kinase (pTAK1) in neurons exhibiting substantial tau pathology in both Alzheimer’s disease and CTE brains, and developed a novel small molecule therapeutic, BNC-1, that shows promising reductions in TAK1 activation, and p-tau accumulation in mouse models of tau pathology and wildtype mice with a CHI. Our goal is to determine an optimal BNC-1 dosage and treatment regimen that significantly reduces TAK1 phosphorylation (Aim 1) and the ensuing tau pathology, neuron degeneration, and behavioral impairments (Aim 2). Given the high prevalence of TBI in older adults, the therapeutic advancement of BNC-1 could significantly reduce the burden of TBI-induced cognitive impairments. Establishing the dose-response relationship and the optimal treatment schedule of BNC-1 is crucial data for a preclinical R01 to validate target engagement, understand the mechanism of action, and conduct pharmacokinetics/pharmacodynamics (PK/PD) testing of BNC-1. If supported by data, our mid-term objective is to advance BNC-1 toward clinical research evaluation for TBI, Alzheimer’s disease, and other tauopathies.