Cerebral tau pathology in murine models of closed-head traumatic brain injury: A narrative review and comparison with human disease

Abstract

Traumatic brain injury (TBI) constitutes a significant public health problem, as a leading cause of death and disability worldwide. Epidemiological evidence indicates that TBI is a major risk factor for several neurodegenerative disorders characterized by the pathological accumulation of the tubulin-associated unit (tau) protein. To delineate the underlying mechanisms promoting tau pathology following TBI, murine models are increasingly utilized as they provide the ability to conduct detailed histopathological analyses under well-controlled conditions. Closed-skull TBI models are frequently employed to mimic the most common type of TBI encountered in clinical settings; however, relatively few studies have examined tau pathology in these models. In this review, we aim to summarize the current data on tau pathologies observed in murine models of closed-head TBI and compare them with human disease. In summary, murine TBI models replicate many important aspects of tau pathology seen in human TBI. This includes phosphorylation of tau protein at similar sites as in human tau, accumulation of hyperphosphorylated tau (pTau) in both neurons and astrocytes, formation of tau oligomers, presence of pTau in similar cerebral locations as in human TBI, and the deregulation of similar tau-related kinases and phosphatases (e.g., glycogen synthase kinase-3, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and protein phosphatase-2B). Nevertheless, the formation of paired helical filaments and neurofibrillary tangles appears to be limited to tau transgenic models.