Production, accumulation and clearance of amyloid-beta after experimental traumatic brain injury

Traumatic brain injury (TBI) increases levels of the toxic peptide amyloid-beta (Aβ) in the brain. As acute accumulation of Aβ may contribute to secondary injury after TBI, and chronic accumulation of Aβ may underlie the increased risk of developing Alzheimer's disease (AD) after TBI, we investigated production, aggregation, and clearance of Aβ after experimental TBI to identify the mechanisms underlying Aβ accumulation in the brain after injury.;Aggregation of Aβ can lead to formation of particularly toxic soluble Aβ oligomers, thought to be the pathogenic species in AD. To determine whether Aβ aggregates into Aβ oligomers after TBI, we exposed triple transgenic (3xTg) AD model mice to controlled cortical impact injury and measured levels of soluble, insoluble and oligomeric Aβ. We found that TBI rapidly increased Aβ production and levels of soluble, insoluble, and oligomeric Aβ in the injured cortex, demonstrating that toxic Aβ oligomers are increased in the brain after TBI.;Levels of Aβ decreased over time—despite continued increased production, suggesting an endogenous mechanism of Aβ clearance after TBI. Apolipoprotein E (apoE) has been shown to be a key facilitator of Aβ clearance. We measured levels of soluble apoE in the injured cortex of both 3xTg and C57BL/6 mice after TBI and found that levels of soluble apoE were reduced at 1 day, the timepoint at which Aβ levels peaked. This inverse relationship remained throughout the 7d post-injury period, with Aβ decreasing as levels of apoE recovered and increased. Pharmacologically increasing levels of apoE enhanced Aβ clearance after TBI and decreased levels of Aβ, but not in Apoe-/- mice, indicating that apoE mediates Aβ clearance after TBI.;Carriers of the ε4 polymorphism in the APOE gene have worsened outcome after TBI and increased risk of AD. We exposed human APOE3- and human APOE4-targeted replacement mice to TBI to investigate the influence of human APOE genotype on Aβ clearance after TBI. We found that apoE-mediated Aβ clearance after TBI was impaired in APOE4-TR mice, leading to increased accumulation of Aβ in the brain. This may explain increased risk of AD and worsened outcome after TBI in this population.