Nayab, F. | bioRxiv Science

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2022

A single closed head injury in mice induces chronic, progressive white matter atrophy and increased phospho-tau expressing oligodendrocytes

Traumatic brain injury (TBI) acutely damages the brain; this injury can evolve into chronic neurodegeneration. While much is known about the chronic effects arising from multiple mild TBIs, far less is known about the long-term effects of a single moderate to severe TBI. We found that a single moderate closed head injury to mice induces diffuse axonal injury within 1-day post-injury (DPI). At 14 DPI, injured animals have atrophy of ipsilesional cortex, thalamus, and corpus callosum, with bilateral atrophy of the dorsal fornix. Atrophy of the ipsilesional corpus callosum is accompanied by decreased fractional anisotropy and increased mean and radial diffusivity that remains unchanged between 14 and 180 DPI. Injured animals increased density of phospho-tau immunoreactive (pTau+) cells in the ipsilesional cortex and thalamus, and bilaterally in corpus callosum. Between 14 and 180 DPI, atrophy occurs in the ipsilesional ventral fornix, contralesional corpus callosum, and bilateral internal capsule. Diffusion tensor MRI parameters remain unchanged in white matter regions with delayed atrophy. Between 14 and 180 DPI, pTau+ cell density increases bilaterally in corpus callosum, but decreases in cortex and thalamus. The location of pTau+ cells within the ipsilesional corpus callosum changes between 14 and 180 DPI; density of all cells increases including pTau+ or pTau- cells. Greater than 90% of the pTau+ cells are in the oligodendrocyte lineage in both gray and white matter. Density of thioflavin-S+ cells in thalamus increases by 180 DPI. These data suggest a single closed head impact produces multiple forms of chronic neurodegeneration. Gray and white matter regions proximal to the impact site undergo rapid atrophy. More distal white matter regions undergo chronic, progressive white matter atrophy with an increasing density of oligodendrocytes containing pTau. These data suggest that the chronic neurodegeneration arising from a single moderate CHI differs greatly from the chronic traumatic encephalopathy produced by multiple mild head injuries. HighlightsGray and white matter atrophy begins within 14 days after a single closed head injury White matter atrophy progresses between 14 and 180 days post injury with minimal changes in diffusion tensor MRI parameters. CHI increases the density of oligodendrocytes with perinuclear accumulation of phosphorylated tau Thioflavin-S+ cells increase in thalamus at 180 days post injury

neuroscience↗