Tau Isoform Expression Drives Disease Outcomes Following a Single Closed Head Injury

Abstract

Tau protein has been implicated as an important mediator of traumatic brain injury (TBI). Adult human brain expresses 6 tau isoforms expressing 3 (3R) or 4 (4R) microtubule binding sites; adult mouse brain expresses only 4R tau. A role for tau isoform expression on TBI disease course is tested using wild-type C57/BL6 mice (WT) and C57/BL6 with a knocked-in human tau coding region (MAPTKI). Uninjured WT and MAPTKI mice have similar brain histology and behavior as they age. At subacute times (14 days post-injury (DPI)), injured MAPTKI mice have less white matter damage with similar neuronal loss as WT. At chronic times (90DPI), MAPTKI mice demyelinate while WT mice remyelinate. At 14DPI, tau phosphorylation differs between WT and MAPTKI mice. At 90DPI, thioflavin-S+ protein aggregates in MAPTKI corpus callosum are higher than WT. At 14 or 90DPI, WT and MAPTKI mice acquire Barnes maze, WT retention is impaired at 14DPI and MAPTKI retention impaired at 90DPI. At 14DPI, only MAPTKI mice acquire and retain active place avoidance; at 90DPI, only WT mice acquire active place avoidance. At 14DPI, only injured MAPTKI mice acquire alternating T-maze. These data suggest that WT and MAPTKI differ in both subacute and chronic disease course. At 14DPI, WT mice have greater white matter damage and behavioral impairments than MAPTKI mice. At 90DPI, impairments in WT mice partially recover, yet worsen in MAPTKI mice. This data suggests that 3R tau isoform expression alters the disease course of head injury. HighlightsPost-injury disease course of MAPTKI mice expressing 3R and 4R tau differs from wild-type mice expressing only 4R tau. At subacute times post-injury, MAPTKI mice have less white matter, yet similar gray matter, injury than wild-type mice. At chronic times post-injury, white matter damage in MAPTKI worsens. At subacute times post-injury, MAPTKI mice have fewer behavioral deficits than wild type mice. At chronic times post-injury, MAPTKI mice develop behavioral deficits not present at subacute times.