Abstract
Traumatic brain injury (TBI) is a major environmental risk factor for Alzheimer's disease. Intracellular accumulations of amyloid-β and tau proteins have been observed within hours following severe TBI in humans. Similar abnormalities have been recapitulated in young 3xTg-AD mice subjected to the controlled cortical impact model (CCI) of TBI and sacrificed at 24 h and 7 days post injury. This study investigated the temporal and anatomical distributions of amyloid-β and tau abnormalities from 1 h to 24 h post injury in the same model. Intra-axonal amyloid-β accumulation in the fimbria was detected as early as 1 hour and increased monotonically over 24 hours following injury. Tau immunoreactivity in the fimbria and amygdala had a biphasic time course with peaks at 1 hour and 24 hours, while tau immunoreactivity in the contralateral CA1 rose in a delayed fashion starting at 12 hours after injury. Furthermore, rapid intra-axonal amyloid-β accumulation was similarly observed post controlled cortical injury in APP/PS1 mice, another transgenic Alzheimer's disease mouse model. Acute increases in total and phospho-tau immunoreactivity were also evident in single transgenic TauP301L mice subjected to controlled cortical injury. These data provide further evidence for the causal effects of moderately severe contusional TBI on acceleration of acute Alzheimer-related abnormalities and the independent relationship between amyloid-β and tau in this setting.
Highlights
Moderate to severe traumatic brain injury (TBI) can accelerate cognitive decline and increases the risk of dementia of the Alzheimer’s type [1,2,3,4,5]
Acute axonal Ab pathology post cortical impact model (CCI) in 3xTg-Alzheimer’s disease (AD) mice Axonal Ab pathology is a characteristic feature of human traumatic axonal injury [9,13,20]
By staining the brains of injured and agematched, uninjured 3xTg-AD mice with several different antibodies specific for Ab, we have previously shown that this injury paradigm caused intra-axonal Ab accumulation at 24 h post TBI [15]
Summary
Moderate to severe traumatic brain injury (TBI) can accelerate cognitive decline and increases the risk of dementia of the Alzheimer’s type [1,2,3,4,5]. Intracellular accumulation of Ab, extracellular deposition of diffuse Ab plaques, and aggregation of tau have been observed in humans, sometimes within hours post severe injury [7,8,9,10,11,12,13]. We found intra-axonal Ab accumulation and accelerated tau pathology in these mice at 1 day and 7 days post TBI. Our immunostaining using several antibodies including 3D6 established that this post-injury axonal immunoreactivity was specific for Ab [15], as 3D6 does not recognize APP [17]. We demonstrate that CCI causes acute Ab accumulation in young APP/PS1 mice [18], which harbor a different PS1 mutation from 3xTg-AD mice, and acutely accelerates tau pathology in TauP301L transgenic mice [19].
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