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Advanced Neurology Tau pathology in murine TBI

TBI is commonly classified into closed-head injury (i.e., the conditions. In addition, underlying molecular mechanisms
cranium remains intact) and penetrating brain injury. can be assessed through genetic manipulation without
Closed-head injuries, such as those sustained from falls, confounding comorbid conditions. However, limited
direct head impacts, motor vehicle crashes, and assaults, studies have investigated tau pathology following TBI in
represent the most common form of TBI. While TBI has mice, creating a gap in our understanding of how well
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been traditionally classified as mild, moderate, and severe, these models replicate the tau pathology observed in
it is increasingly recognized that TBI causes a spectrum of human disease. This review aims to summarize reported
micro- and macroscopic brain pathologies that lead to a tau pathology within the context of murine closed-skull
variety of symptoms, impairments, and recovery patterns TBI models and to compare these findings with those
across injury severities, including after seemingly mild observed in human disease.
injuries. Importantly, epidemiological evidence indicates
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that, in addition to the immediate effects of the injury, 2. Methods
TBI significantly increases the risk of several chronic Using narrative review methods, we searched PubMed
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progressive neurodegenerative disorders, many of which and performed manual searches of references from the
are associated with cognitive decline and dementia. 6-10 retrieved literature. Our PICO model was defined as
While the association between TBI and neurodegenerative follows: P: Wild-type mice and tau mutant mice; I: Closed-
diseases is strongest for moderate-to-severe injuries, there skull TBI model; C: Human TBI and human tauopathy; O:
is increasing evidence that even milder TBIs, particularly Tau isoforms, post-translational modifications of tau, tau
when repeated, can also increase this risk. 11,12 hyperphosphorylation, tau expression and structure, tau
The increased risk of neurodegenerative diseases antibodies, tau kinases and phosphatases, tau aggregation,
associated with TBI implies that an acute injury may initiate and interaction between tau and TDP-43. Our search
a detrimental cascade of events that cause and promote for the “I” (intervention) term included only papers that
long-term pathology. However, the exact mechanisms referenced tau protein assessment in mice subjected to
through which TBI causes chronic neurodegeneration closed-skull TBI, including blast injuries.
and dementia remain poorly understood, and there are
currently no specific treatments available to prevent 3. Review
or ameliorate these conditions. Thus, investigating the 3.1. Common neurodegenerative diseases
mechanistic link between TBI and neurodegeneration associated with tau pathology and TBI
to uncover novel therapeutic targets is a public health Tauopathies constitute a group of neurodegenerative
priority. 13 diseases characterized by pathological tau aggregation
Since the initial identification of white matter injury within neurons and glial cells. While over 20 distinct types
as a unique consequence of TBI, it has become clear of human tauopathies have been identified, they can be
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that axonal pathology occurs early across various injury broadly classified into primary (i.e., tau deposition is the
severities. 15-18 While traumatic axonal injury is believed primary pathology) and secondary tauopathies (i.e., tau
to underlie many of the observed neurological deficits deposition is considered a response to other pathological
following TBI, it has been proposed that axonal injury may proteins or events). 22,24,25 Further, tauopathies have been
also serve as a trigger for subsequent neurodegenerative characterized according to the predominant pattern of tau
processes. After TBI, disruption of the axonal deposition, cell type involvement, dominant tau isoforms,
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cytoskeleton leads to the release of the tubulin-associated and distribution of tau across different brain regions
unit (tau) protein, providing a mechanistic link to TBI- (Table 1).
associated neurodegenerative disorders, most of which are In addition to increasing the risk for various tauopathies,
characterized by the accumulation of pathogenic forms of repetitive TBI (rTBI) triggers a unique secondary tauopathy
tau, collectively termed tauopathies. 7,8,19-22 Despite the clear characterized by delayed neurodegeneration and cognitive
epidemiological link between TBI and tauopathies, the decline, termed chronic traumatic encephalopathy
specific mechanisms driving tau pathology and its possible (CTE). 26,27 CTE is associated with progressive cognitive
association with axonal and neuronal degeneration and and behavioral dysfunction, including impaired short-
clinical outcomes remain incompletely understood. term memory, difficulties in higher-order decision-
Murine closed-skull TBI models are frequently utilized making, apathy, emotional instability, and depression.
to interrogate the mechanisms of TBI-associated pathology The diagnosis of CTE is presently based on consensus
as they allow for detailed, longitudinal analyses in a criteria that include information on a distinct pattern of
temporally accelerated fashion and under well-controlled tau deposition and a history of exposure to repetitive head

Volume 3 Issue 3 (2024) 2 doi: 10.36922/an.3213