Alzheimer's disease (AD) is a neurodegenerative disorder characterized 
pathologically by progressive neuronal loss, extracellular plaques containing 
the amyloid-β (Aβ) peptides, and neurofibrillary tangles composed of 
hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, 
affecting its phosphorylation and therefore aggregation state. One of the major 
risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aβ and 
diffuse extracellular plaques occur in ∼30% of human subjects after severe TBI. 
Intra-axonal accumulations of tau but not tangle-like pathologies have also been 
found in these patients. Whether and how these acute accumulations contribute to 
subsequent AD development is not known, and the interaction between Aβ and tau 
in the setting of TBI has not been investigated. Here, we report that controlled 
cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aβ accumulations 
and increased phospho-tau immunoreactivity at 24 h and up to 7 d after TBI. 
Given these findings, we investigated the relationship between Aβ and tau 
pathologies after trauma in this model by systemic treatment of Compound E to 
inhibit γ-secretase activity, a proteolytic process required for Aβ production. 
Compound E treatment successfully blocked posttraumatic Aβ accumulation in these 
injured mice at both time points. However, tau pathology was not affected. Our 
data support a causal role for TBI in acceleration of AD-related pathologies and 
suggest that TBI may independently affect Aβ and tau abnormalities. Future 
studies will be required to assess the behavioral and long-term 
neurodegenerative consequences of these pathologies.