Maternal Traumatic Brain Injury Increases Fetal Brain Cis p-tau Levels: Evidence for Potential Transplacental Effects...

Traumatic brain injury (TBI) is a well-established risk factor for Alzheimer's disease-related tauopathy. However, whether maternal TBI can lead to transgenerational transmission of pathogenic tau to offspring remains unknown. This study examines whether maternal Traumatic brain injury (TBI) induces pathogenic tau transfer to offspring, impairing fetal brain development. TBI was induced in pregnant Balb/C mice prior to pregnancy using a weight-drop model, while the sham group underwent anesthesia without injury, and the fetal brains were analyzed for cis p-tau using immunofluorescence (IF) and Western blotting (WB). Maternal anxiety post-TBI was assessed via the Elevated Plus Maze (EPM). Compared with the sham group, maternal TBI resulted in 4.25 and 5.81-fold increase in cis p-tau aggregation in embryonic and fetal brains, respectively (F(2,12) = 68.45, p < 0.001; F(2,12) = 102.34, p < 0.0001), and protein levels showed 3.13- and 6.79-fold increases (F(2,12) = 45.12, p < 0.001; F(2,12) = 89.67, p < 0.0001). This was accompanied by a significant increase in apparent transfer efficiency of p-tau to fetal brains (t(8) = 12.50, p < 0.0001). EPM assessment revealed that TBI-induced dams spent significantly more time in the open arms compared with sham (t(8) = 2.65, p = 0.029), suggesting reduced anxiety-like behavior or increased risk-taking. Maternal serum p-tau181 and fetal cis p-tau showed a positive but non-significant correlation (r(3) = 0.78, p = 0.120). These changes were associated with IL-6 and TNF increased by 2.8-fold (t(8) = 4.22, p = 0.003) and 1.8-fold (t(8) = 2.45, p = 0.040), respectively. These findings demonstrate a significant increase in apparent p-tau transfer efficiency from maternal serum to fetal brain following maternal TBI, although the correlation between maternal serum p-tau181 and fetal brain cis p-tau did not reach statistical significance.