Repeated mild spinal cord contusions exacerbate tauopathy development in PS19 mice

Growing evidence indicates that traumatic brain injury constitutes a significant risk factor for the development of age-related tauopathies, yet the consequences of repeated mild spinal cord injuries (rmSCI) remain insufficiently explored. In this context, we developed a mouse model undergoing two successive mild cervical contusions during young adulthood, which do not produce immediate functional motor deficits, thereby mimicking real-life conditions of occupational- or sports-related trauma. rmSCI were induced in PS19 (hTau^P301S) mice developing late-onset tauopathy in the brain and in the spinal cord. The consequences of rmSCI were assessed on motor outcomes and tauopathy signature in injured PS19 mice during ageing. rmSCI exacerbated age-dependent motor deficits and significantly increased tau hyperphosphorylation on the pSer422 and pSer202/Thr205 epitopes. Pathological changes, initially confined to the epicenter of the contusions, extended along a caudo-rostral axis reaching the thalamus. While rmSCI did not modify intraspinal tau aggregation, spinal cord-derived protein extracts displayed enhanced seeding activity in vitro. Although causality was not established with tau hyperphosphorylation status, early response towards mild spinal contusions included p38 MAPK activation, glial activation and upregulation of interferon-stimulated genes. Together, these data identify rmSCI as a previously underappreciated modifier of tau pathology and disease progression. Moreover, this study provides a novel experimental link between mild central nervous system injuries and exacerbation of tauopathy and suggests the involvement of type I interferon signalling or sustained glial activation. Ultimately, these findings underscore the importance of preventing even mild spinal injuries in individuals at risk of tauopathy.