Repetitive Mild Traumatic Brain Injury Augments Tau Pathology and Glial Activation in Aged hTau Mice

Extensive tau-immunoreactive neurons and glial cells associated with chronic traumatic encephalopathy (CTE) have been documented in the brains of some professional athletes and others with a history of repetitive mild traumatic brain injury (r-mTBI). The neuropathology and tau involvement in mTBI have not been extensively studied in animal models, particularly in aged animals. We investigated the effects of single mTBI (s-mTBI) and r-mTBI in 18-month-old hTau mice, which express wild-type human tau isoforms on a null murine tau background (n = 3-5 per group). At this age, hTau mice already demonstrate tau pathology, but there was a significant increase in phospho-tau immunoreactivity in response to r-mTBI, but not to s-mTBI, as determined using multiple phospho-tau-specific antibodies. Repetitive mTBI also resulted in a marked increase in astrocyte/microglia activation notably in the superficial layer of the motor/somatosensory cortex and the corpus callosum. We did not observe the perivascular tau pathology, neuritic threads, or astrocytic tangles that are commonly found in human CTE. The increase in phosphotau in the r-mTBI mice suggests that this may be a useful model for investigating further the link between mTBI, particularly r-mTBI, and tau pathobiology in CTE and in understanding responses of the aged brain to mTBI.