Converging Pathways: Neuroimmunology of Tauopathy and Mild Traumatic Brain Injury

Age-related neurodegenerative diseases impact over 60 million people worldwide with the number steadily increasing each year as the global population ages. Despite years of research and many clinical trials, no therapeutic has proven efficacious at addressing disease progression. The vast heterogeneity of these diseases makes uncovering etiology challenging. Specific genetic and environmental factors, however, have been identified as risk factors. For example, repetitive brain injury strongly correlates with the neurodegenerative disease Chronic Traumatic Encephalopathy. Because rising evidence has linked innate and adaptive immunity to neurodegenerative diseases, in this thesis, I set out to map the immune responses of a primary tauopathy and repeat head injury. Using high parameter flow cytometry and RNA sequencing of spinal cords from late stage P301S tauopathy mice, I found that primary tauopathy drives a microglial transition toward an antigen-presenting phenotype as well as an increase of T lymphocytes. Multiplex immunohistochemistry of these cords, in addition to brain sections from humans with Chronic Traumatic Encephalopathy and Parkinsonian-Dementia Complex of Guam, showed direct engagement of Iba-1+ microglia by clusters of CD8+ T cells. Interestingly, ablating CD8+ T cells resulted in greater phosphorylated tau deposition, accelerated disease progression, and an increase of all ‘sick’ microglia subsets including a previously unidentified microglia population, possessing neuronal and viral expression pathways. To elucidate connections between repetitive brain injury and primary tauopathy, I studied the acute impact of a 24-hour reinjury in a murine model of mild traumatic brain injury. I discovered that reinjury induced free radical-mediated breakdown of the glia limitans superficialis, a layer of astrocytic end-feet separating the meninges and the CNS parenchyma. Following a single injury, microglia caulk damage within the glia limitans superficialis but fail to do so in the reinjury paradigm. Breach and scarring of this crucial barrier surface are linked to degenerative diseases, so rescue of it is of utmost therapeutic importance. Scavenging reactive oxygen species and inhibiting the NOX2 isoform of the NADPH oxidase complex reduced cortical cell death and preserved the glia limitans superficialis after head injury. Collectively, this work provides novel insights into shared immune phenomena across neurodegenerative diseases and head injury. It presents possible therapeutic targets for both with the hopes of reducing the incidence of injury-induced neurodegenerative diseases.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Mason, Hannah

Advisor dc:contributor.advisor

• Paulsen, Ole

• neuroimmunology
• microglia
• neurodegeneration
• traumatic brain injury

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0003-1701-4655

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/340152