Detrimental Effect of Genetic Inhibition of B-Site App-Cleaving Enzyme 1 on Functional Outcome after Controlled Cortical Impact in Young Adult Mice

Abstract

β-Amyloid (Aβ) peptides, most notably associated with Alzheimer's disease, have been implicated in the pathogenesis of secondary injury after traumatic brain injury (TBI). A prior study has demonstrated that blocking the β-site amyloid precursor protein (APP)-cleaving enzyme 1 (Bace1) required for production of Aβ from APP improved functional and histologic outcomes after controlled cortical impact (CCI) in aged mice. However, the majority of patients with severe TBI are young adults under the age of 40. Prior experimental models have suggested age-dependent differences in Aβ clearance, and a recent study in our lab suggests that young animals remediate acute elevations in Aβ after CCI better than older animals. We therefore tested the hypothesis that Bace1 deletion in young adult mice would not be protective after CCI. Male Bace1 knockout (Bace1(-/-)) and wild-type Bace1(+/+) (C57BL/6) mice (2-3 months old) were subjected to CCI (n=18-23/group) or sham injury (n=10-12/group). Functional outcomes were assessed with wire grip (motor) and the Morris water maze (MWM; spatial memory). Soluble Aβ levels were assessed at 48 h after CCI. Histopathological outcomes were assessed by lesion and hippocampal volume. Clustered ordinal logistic regression showed overall significant impairment in motor performance in injured Bace1(-/-) versus Bace1(+/+) animals (p=0.003). No significant differences in MWM performance were found on repeated-measures ANOVA (p=0.11) between groups. Probe scores were significantly worse in injured Bace1(-/-) versus Bace1(+/+) mice (p=0.0009). Soluble Aβ(40) was significantly lower in ipsilateral hemispheres of Bace1(-/-) than in Bace1(+/+) animals after CCI (0.9 [IQR 0.88-0.94] pmol/g protein versus 3.8 [IQR 2.4-6.0] pmol/g protein; p=0.005). Lesion and hippocampal volumes did not differ between injured groups. The data suggest that therapies targeting Bace1 may need to be tailored according to age and injury severity, as their use may exacerbate functional deficits after TBI in younger or less severely injured patients.