P3-290: Enhanced tau pathology, cerebral atrophy and iron deposition induced by repetitive mild brain injury in a tau transgenic mouse

Abstract

Traumatic brain injury (TBI) is a risk factor for Alzheimer's disease (AD), and repetitive TBI (rTBI) may culminate in dementia pugilistica (DP), a syndrome characterized by progressive dementia, parkinsonism, and the hallmark brain lesions of AD, including neurofibrillary tangles (NFTs), and senile plaques (SPs), suggesting similar pathological pathways between AD and TBI. Although previous study showed that mild rTBI (mrTBI) accelerated the deposition of Aβ in a mouse model of AD–like amyloidosis Tg2576, it is still unclear that mrTBI enhance tau pathology. We examined the effects of mrTBI on AD–like tau pathologies in Tg mice expressing the shortest human tau isoform subjected to mrTBI, causing brain concussion without structural brain damage to simulate injuries linked to DP. Twelve–month–old Tg T44 (n = 18) and wild–type (WT; n = 24) mice were subjected to mrTBI (four times a day, 1 day per week, for 4 weeks; n = 24) or sham treatment (n = 18). Histopathological analysis of mice at 9 months after mrTBI revealed that one of the Tg T44 mice showed extensive telencephalic NFTs and cerebral atrophy. Although the critical difference between that mouse and other T44 remained unclear, the positive iron staining was found only in the brain surface of that mouse. Since iron is a major free radical source and there is circumstantial evidence linking abnormal iron metabolism to mechanisms underlying AD, we speculated that iron deposition might contribute to the enhanced tau pathology. To address this possibility, we micro–injected ferrin chloride (0.5 μl 100mM FeCl3) into the hippocampus of T44 mice (n = 8), and then diachronically examined histological changes for 6 months. However, we could not affirm the enhancement of NFT formation in any FeCl3–injected T44 mice. We cannot conclude that iron directly relates to the enhanced tau pathology, though possibilities that some blood components other than iron, or combination of several blood components including iron, might enhance tau pathology cannot be excluded because the iron–positive staining is convincing evidence of BBB breakdown.