PhD thesis defense in biomedical and pharmaceutical sciences by Nicolas Halloin

Consequences of repeated mild trauma on the spinal cord and the development of tauopathies

Candidate

Nicolas Halloin

Promoter

Prof. Charles Nicaise, UNamur, Department of medicine, Molecular Physiology Research Unit (URPhyM), Laboratory Neurodegeneration and Regeneration (LNR) 

Jury

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

Summary

Population aging has been accompanied by an increasing prevalence of neurodegenerative diseases, including tauopathies. This group of disorders, which notably includes Alzheimer's disease, is characterized by the mislocalization, hyperphosphorylation, and pathological accumulation of the Tau protein, leading to neuronal dysfunction and cell death within the central nervous system. Numerous studies conducted in humans and in various animal models have demonstrated an association between repetitive traumatic brain injuries and the development of a specific tauopathy known as chronic traumatic encephalopathy. This progressive neurodegenerative disease is causally linked to repeated head impacts generating acceleration-deceleration forces within the brain.

Although the brain and spinal cord share many cellular and tissue characteristics, the consequences of spinal cord injuries on the development of tauopathies remain largely underexplored. To address this question, a novel mouse model of repeated mild spinal cord injury was developed using PS19 mice, a transgenic model of tauopathy that recapitulates several features of frontotemporal dementia. Two mild spinal cord contusions (30 kDynes) 3 weeks apart, were performed at two months of age to evaluate their long-term impact on disease progression.

Although these injuries did not induce immediate clinical deficits, detectable tissue damage, or neuronal loss, they elicited a pronounced glial response as well as neuronal and axonal damage, as evidenced by increased circulating neurofilament light chain levels. Longitudinal follow-up revealed an earlier onset of motor and sensory deficits, accompanied by a faster decline in the overall health status of injured animals.

No exacerbation of tau pathology was detected at the early time point (3.5 months of age). However, by 6.5 months of age, a significant increase in the density of hyperphosphorylated Tau species, detected on the epitopes pTau(Ser202/Thr205) and pTau(Ser422), was observed around the lesion epicenter in contused animals. At 9 months of age, this exacerbated tau pathology had spread along the rostrocaudal axis from spinal segments C2 to C7 and extended to the thalamus. Although spinal cord contusions did not alter Tau aggregation, in vitro analyses demonstrated that the insoluble protein fraction extracted from the injured spinal cord exhibited enhanced Tau seeding activity.

Although no direct causal relationship could be established, histological, biochemical, and transcriptomic analyses suggest that microglia, type I interferon signaling, and the p38 MAP kinase pathway contribute to the promotion of Tau hyperphosphorylation.

Taken together, these findings identify mild spinal cord injury as a previously underappreciated risk factor for the development and progression of tauopathies. They further support accumulating evidence implicating neuroinflammation, particularly microglial activation and type I interferon signaling, in the exacerbation of Tau pathology. Finally, this work highlights the importance of long-term monitoring of individuals exposed to spinal cord injuries, even those of mild severity, owing to their potentially increased risk of developing Tau-related neurodegenerative disorders.