Studies in Mice and Patients to Understand the Role of Tau Pathology in Driving Neurodegeneration After Traumatic Brain Injury

Vegliante, Gloria (2023). Studies in Mice and Patients to Understand the Role of Tau Pathology in Driving Neurodegeneration After Traumatic Brain Injury. PhD thesis The Open University.



Traumatic brain injury (TBI) is a global public health issue that afflicts 55 million people worldwide. It represents a huge burden for the health system, and a leading cause of injury-related death and disability, with devastating impact on individuals and society. TBI is a complex disease characterised by dynamic pathophysiological adaptive and maladaptive processes that may predispose to chronic neurodegeneration and increase risk of dementia later in life including Alzheimer’s disease (AD). However, the mechanisms driving the transition from the acute biomechanical impact to late neurodegeneration still need to be fully addressed.

The development of progressive proteinopathies is a shared feature of dementia and TBI. In particular, tau pathology has sparked our interest being a hallmark of AD and pathognomonic feature of chronic traumatic encephalopathy. In the present study we document the presence of tau pathology in human brain contusion samples surgically removed early after severe TBI in patients. We provide evidence that human TBI-induced tau (tauTBI) has self-templating properties and spreads throughout the brain causing a widespread tau pathology that is associated with synaptic dysfunction and cognitive impairment. Moreover, we show that tauTBI can be horizontally transmitted to naïve mice by intracerebral inoculation, causing memory deficits. Thus, human tauTBI holds prion-like properties, suggesting a mechanism by which an acute biomechanical impact may predispose to neurodegeneration in patients. We also show an impairment of proteostatic mechanisms in chronic TBI mice, thus further contributing to tau accumulation later in life. Interestingly, tau deficiency reduces the physiological cognitive aged-related decline in mice. Finally, we exploit the C. elegans model to demonstrate that the bio-inspired multitarget hexapeptide Aβ1-6A2V(D), acting against amyloid β and tau, could represent an innovative pharmacological approach to counteract pathological aggregates formation and mitigate the progression of dementia and post-traumatic neurodegenerative processes.

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