Abstract

Population aging is accompanied by an increase in the prevalence of neurodegenerative diseases, including tauopathies. This family of diseases, which includes Alzheimer’s disease, is characterized by the mislocalization, hyperphosphorylation, and accumulation of the tau protein in a pathological form, leading to neuronal dysfunction and ultimately neuronal death within the central nervous system. Numerous studies conducted in humans and in various animal models have demonstrated an association between repeated head trauma and the development of a specific tauopathy, chronic traumatic encephalopathy. This progressive neurodegenerative disease is attributed to repeated exposure to impacts to the head that generate acceleration-deceleration forces in the brain.

Although the brain and spinal cord share many cellular and tissue characteristics, the consequences of spinal cord trauma on the development of tauopathies remain largely unexplored. To investigate this question, a new mouse model of repeated mild spinal cord trauma was developed in the PS19 mouse, a transgenic model of tauopathy that replicates several characteristics of frontotemporal dementia. Two low-intensity spinal cord contusions (30 kDynes), administered three weeks apart, were performed at two months of age to assess their impact on the long-term progression of the disease.

Although these injuries induce neither immediate clinical deficits, nor detectable tissue lesions, nor neuronal loss, they elicit a marked glial response as well as neuronal and axonal damage, as evidenced by increased circulating concentrations of neurofilament light chains. Longitudinal follow-up of the animals revealed an earlier onset of motor and sensory deficits, associated with an accelerated decline in their overall health.

In the short term (3.5 months), no worsening of tauopathy was observed. However, at 6.5 months of age, a significant increase in the density of hyperphosphorylated forms of tau, detected by the pTau(Ser202/Thr205) and pTau(Ser422) antibodies, was observed near the epicenter of the lesion in the contusion-injured animals. By 9 months, this exacerbation of the pathology had spread along the rostral-caudal axis, between spinal cord segments C2 and C7, as well as to the thalamus. Although spinal cord injuries did not alter Tau protein aggregation, in vitro analyses showed that the insoluble protein fraction extracted from the spinal cord of contusion-injured animals possessed greater recruitment capacity.

Although no direct causal link could be established, histological, biochemical, and transcriptomic analyses suggest the involvement of microglia, type I interferon signaling, and the p38 MAP kinase pathway in stimulating Tau hyperphosphorylation.

Taken together, these results highlight a previously largely underestimated role of mild spinal cord injuries as a factor promoting the development and progression of tauopathies. They also reinforce existing literature suggesting that neuroinflammation—and more specifically, microglial activation and type I interferon signaling—contributes to the progression of these diseases. Finally, this study underscores the importance of long-term follow-up for individuals exposed to spinal cord injuries—even mild ones—due to the potential increased risk of developing neurodegenerative diseases involving the Tau protein.

Jury

  • Prof. Pascal KIENLEN-CAMPARD (UCLouvain)
  • Prof. Karelle LEROY (ULB)
  • Prof. Aurélie LADANG (ULiège)
  • Prof. Charles NICAISE (UNamur)
  • Prof. Patsy RENARD (UNamur), Chair
  • Prof. Laurence RIS (UMons)