Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein

Abstract

Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer’s disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrPC) and amyloid-β oligomers (Aβo). This PrPC-Aβo complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrPC accumulate Aβ, but show normal survival and no loss of spatial learning and memory suggesting that PrPC functions downstream of Aβo production but upstream of intracellular toxicity within neurons. Since AD and traumatic brain injury (TBI)-linked chronic traumatic encephalopathy are tauopathies, we examined whether similar mechanistic pathways are responsible for both AD and TBI pathophysiologies. Using transgenic mice expressing different levels of PrPC, our studies investigated the influence and necessity of PrPC on biomarker (total-tau [T-Tau], P-Tau, GFAP) levels in brain and blood as measured biochemically following severe TBI in the form of severe closed head injury (sCHI). We found that following sCHI, increasing levels of T-Tau and P-Tau in the brain were associated with the PrPC expression levels. A similar relationship between PrPC expression and P-Tau levels following sCHI were found in blood in the absence of significant T-Tau changes. This effect was not seen with GFAP which increased within 24 h following sCHI and progressively decreased by the 7 day time point regardless of the PrPC expression levels. Changes in the levels of all biomarkers were independent of gender. We further enhanced and expanded the quantitation of brain biomarkers with correlative studies using immunohisochemistry. We also demonstrate that a TBI-induced calpain hyperactivation is not required for the generation of P-Tau. A relationship was demonstrated between the presence/absence of PrPC, the levels of P-Tau and cognitive dysfunction. Our studies suggest that PrPC is important in mediating TBI related pathology.

Altered levels of plasma neuron‐derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury

“…2). PRPc binds oligomeric Aβ peptides with high affinity in a neurotoxic trimolecular complex with Fyn kinase (43, 44). The mean NDE levels of PRPc were increased significantly above those of controls with similar fold‐increases in acute and chronic repetitive mTBI (Fig.…”

Sex-dependent macromolecule and nanoparticle delivery in experimental brain injury

“…These results were obtained from cohorts with no significant sex-dependent variations in astrogliosis and lesion volume. Numerous pre-clinical TBI studies report a female neuroprotective effect implicating estrogen or progesterone mediated mechanisms 58-61 , but a few studies report no impact of sex on the outcome 62,63 . In contrast, clinical studies cite worse outcomes for females compared to males [64][65][66][67][68] .…”

The ecology of chronic wasting disease in wildlife

“…Another hypothesis suggests that prion formation might be promoted or accelerated by traumatic brain injury, which potentially damages tissues and/or axons facilitating metabolic, ionic, and cytoskeletal damage, or causes transcriptional errors that trigger improper folding and clumping of proteins inside nerve cells in the brain (e.g. neurons or astrocytes), as observed for tau protein (Woerman et al, 2016;Rubenstein et al, 2017;Edwards et al, 2019).…”

“…Chronic trauma has not been studied in the context of CWD in animals. However, this phenomenon could mirror the effects of traumatic brain injury in human neurodegenerative diseases, such as chronic traumatic encephalopathy produced by the accumulation of misfolded aggregates composed of the tau protein (Woerman et al, 2016;Rubenstein et al, 2017;Edwards et al, 2019). Thus, chronic trauma may have played a role in the origin of CWD and in recent 'spontaneous' CWD reports in Scandinavia (Benestad et al, 2016;Evira, 2018;Vikøren et al, 2019), although this remains speculative and further research is required.…”