Fig. 7.

Eliminating cis P-tau in rmTBI mice with cis mAb prevents the development of a range of pathological features resembling those found in human CTE. Mice were subjected to seven mild TBI events over 9 days and were treated with cis mAb or IgG isotype control over 4 months, followed by 2 months of washout, before assaying pathologies in different brain regions a, b. Blue arrows, rmTBI; black arrows, antibody injection; green line, functional, or pathological assays. Cis mAb treatment of rmTBI mice eliminated induction and spreading of cis P-tau and total tau c, d, prevented the development and spreading of axonal pathology e, tau oligomerization f, APP accumulation g, GFAP-positive astrocyte h, Iba-positive microglia i, TDP-43 pathology with increased cytoplasmic mislocalization of TDP-43 j−l. Line graphs showing the relative IF intensity of TDP-43 across a single cell k, l (Blue line, DAPI; red line, TDP-43). Cis mAb treatment also prevented the demyelination as detected by CNPase IF m, n, and neuronal loss o in different brain regions. Shorter exposure of ECL for total tau immunoblots in c was used due to a huge increase in total tau in rmTBI mice, as expected because cis P-tau is resistant to protein degradation. Microscope images corresponded to the medial prefrontal cortex of sham (left), rmTBI + IgG (middle), and rmTBI + cis mAb (right) with quantification data in different brain regions being present at right panels. Inset images are the high magnification image of selected area denoted by the white. Scale bar, 40 μm. Red arrows point to axonal bulb in Gallyas silver staining. mPFC, medial prefrontal cortex; HC, hippocampus; Thal, thalamus; BLA, basolateral amygdala; CC, corpus callosum; IC, internal capsule; Cb, cerebellum. ND, not detectable; NS, not significant. Brains from 4−5 WT male mice were studied in immunohistochemistry per group. The data are presented as means ± SEM. The p-values were calculated using unpaired two-tailed parametric Student’s t-test. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001