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Advanced Neurology Tau pathology in murine TBI

3.7. rTBI may promote the formation of pTau with between 4 weeks and 6 months post-injury. 95,100-102
properties that can promote aggregation and The P301S (PS19) transgenic mouse model uses the
spread prion protein promoter (Prnp) to express 1N4R hTau with

Detection of tau pathology at sites distant from the initial the P301S mutation, which increases the protein’s tendency
injury in later stages could be related to the secondary to aggregate. In this model, mutant tau is expressed
spreading of pathological tau aggregates. 92,93 While this at 5 times the level of endogenous mouse tau. In the
concept is well developed for human cases, it is less absence of TBI, PS19 mice develop NFT-like inclusions by
certain whether closed-head TBI models in wild-type 6 months and exhibit significant neuronal loss and brain
mice replicate this pathology. Proof-of-concept that TBI atrophy by 8 months, principally in the hippocampus
induces pTau with properties promoting accumulation but also in the neocortex and entorhinal cortex. This
and spread stems from observations where injection of NFT-like pathology is accompanied by microgliosis and
pTau-enriched brain tissue lysate (obtained from animals astrocytosis, but not by amyloid plaques. Interestingly,
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subjected to controlled cortical impact) into the brains of although PS19 mice are prone to tau pathology, rTBI
wild-type mice triggered widespread pTau accumulation does not appear to alter this pathology, with both TBI
and tau aggregate formation. Moreover, following murine and sham-operated PS19 animals exhibiting similar levels
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closed-skull TBI, sarkosyl-insoluble tau aggregates have of pTau. Moreover, rTBI does not seem to exacerbate
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been detected as early as 24 – 48 h, which persisted for the behavioral deficits, as no significant differences were
up to 6 months. 36,94,95 Nevertheless, conclusive proof that observed between PS19 mice subjected to rTBI and those
closed-skull TBI triggers tauopathy that spreads to initially who underwent sham surgeries. However, PS19 animals
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unaffected brain areas in wild-type mice is still lacking. with TBI exhibited more pronounced neuroinflammatory
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Several lines of data suggest that rTBI may give rise responses compared to wild-type TBI animals. Increased
to pTau species that differ in their properties to promote levels of pTau pathology in homozygous PS19 mice led
persistent Tau pathology. For example, tau oligomers to worsened corpus callosum atrophy from 6 weeks to
obtained from wild-type mouse brains subjected to rTBI 4 months after rTBI. 105
exhibited greater neurotoxicity in primary neuron cultures The 3xTg mouse model expresses three gene mutations
as well as reduced synaptic integrity, vesicular release, and associated with familial AD (APP Swedish, MAPT P301L,
long-term potentiation as compared to oligomers obtained and PSEN1 M146V). These mice develop age-related,
after a single TBI. Moreover, when wild-type mice were progressive neuropathology, including both amyloid
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hippocampally injected with Tau oligomers derived from plaques and NFTs. Amyloid-beta deposits appear in the
the brains of mice subjected to rTBI, hyperphosphorylation frontal cortex by 6 months and become more extensive
and propagation of Tau pathology were observed in the by 12 months. Aggregates of conformationally altered
cortical layers. 96 pTau are typically detected in the hippocampus by 12 –
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3.8. Closed-skull TBI in tau-mutant mice 15 months of age. Transgenic mice subjected to rTBI
show accelerated tau pathology with pTau accumulation in
The absence of 3R isoforms in the adult mouse brain may the hippocampus as early as 9-day post-TBI compared to
affect tau isoform aggregation and could partly explain sham-operated transgenic mice. 107
the relative paucity of studies reporting tau aggregation
following TBI in wild-type mice. 93,97 For example, in human 3.9. Possible interaction between TDP-43 and tau
CTE, tau aggregates include both 3R and 4R isoforms, Transactive response DNA-binding protein 43 kDa (TDP-
and research has demonstrated that the presence of both 43) is an RNA-binding protein that plays a key role in the
isoforms in brain extracts from CTE patients is necessary pathogenesis of amyotrophic lateral sclerosis (ALS) and
for the propagation of tau pathology in HEK cells. 98 frontotemporal dementia (FTD). In addition to FTD, other
In contrast to non-transgenic wild-type animals, mice tauopathies, including AD and CTE, are accompanied by
expressing human Tau (hTau) develop age-associated TDP-43 pathology, which has been suggested to interact
tau pathology, including the redistribution of tau protein with and exhibit pathological synergy with tau. 108-111
to the neuronal cell body and dendrites, as well as the TDP-43 overexpression in an APP/PSEN1 background
accumulation of aggregated paired helical filaments and, transgenic mouse model has been shown to increase
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ultimately, neurofibrillary tangles (NFTs) by 9 – 15 months pTau aggregation. TBI-triggered neuroinflammation
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of age. Several studies have demonstrated that hTau stimulates transcription of TDP-43, which has been
mice subjected to TBI exhibit tau oligomer formation in shown to promote tau phosphorylation by provoking
the cerebral cortex, hippocampus, and subcortical nuclei the expression of GSK3β in APP-transgenic mice. A
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Volume 3 Issue 3 (2024) 7 doi: 10.36922/an.3213