Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model

There is evidence that the amyloid precursor protein (APP) plays an importa nt role in neuronal growth and synaptic plasticity and that its increased e xpression following traumatic brain injury represents an acute phase respon se to trauma. We hypothesized that the previously described increased APP e xpression in response to injury (Van den Heuvel et al., Acta Neurochir. Sup pl. 71., 209-211) is due to increased mRNA expression and addressed this by examining the expression of APP mRNA and APP within neuronal cell bodies o ver time in an ovine head impact model. Twenty-five anesthetized and ventil ated 2-year-old Merino ewes sustained a left temporal head impact using a h umane stunner and 9 normal sheep were used as nonimpact controls. Following postimpact survival periods of 15, 30, 45, 60, and 120 min, brains were pe rfusion fixed in 4% paraformaldehyde and examined according to standard neu ropathological protocol. APP mRNA and antigen expression were examined in 5 -mu m sections by nonisotopic in situ hybridization and APP immunocytochemi stry. The percentage of brain area with APP immunoreactivity within neurona l cell bodies in the impacted animals increased with time from a mean of 7. 5% at 15 min to 54.5% at 2 h. Control brains showed only very small numbers of weakly APP-positive neuronal cell bodies ranging from 2 to 14% (mean 7% ). Increased expression of APP mRNA was first evident in impacted hemispher es at 30 min after impact and progressively increased over time to involve neurons in all sampled regions of the brain, suggesting increased transcrip tion of APP. In contrast, APP mRNA was undetectable in tissue from nonimpac ted sheep. These data show that APP mRNA and antigen expression are sensiti ve early indicators of neuronal injury with widespread upregulation occurri ng as early as 30 min after head impact. (C) 1999 Academic Press.