sAPPa rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury

J. Neurochem. (2012) 122, 208220. Abstract The amyloid precursor protein (APP) is thought to be neuroprotective following traumatic brain injury (TBI), although definitive evidence at moderate to severe levels of injury is lacking. In the current study, we investigated histological and functional outcomes in APP-/- mice compared with APP+/+ mice following a moderate focal injury, and whether administration of sAPPa restored the outcomes in knockout animals back to the wildtype state. Following moderate controlled cortical impact injury, APP-/- mice demonstrated greater impairment in motor and cognitive outcome as determined by the ledged beam and Barnes Maze tests respectively (p < 0.05). This corresponded with the degree of neuronal damage, with APP-/- mice having significantly greater lesion volume (25.0 +/- 1.6 vs. 20.3 +/- 1.6%, p < 0.01) and hippocampal damage, with less remaining CA neurons (839 +/- 245 vs. 1353 +/- 142 and 1401 +/- 263). This was also associated with an impaired neuroreparative response, with decreased GAP-43 immunoreactivity within the cortex around the lesion edge compared with APP+/+ mice. The deficits observed in the APP-/- mice related to a lack of sAPPa, as treatment with exogenously added sAPPa post-injury improved APP-/- mice histological and functional outcome to the point that they were no longer significantly different to APP+/+ mice (p < 0.05). This study shows that endogenous APP is potentially protective at moderate levels of TBI, and that this neuroprotective activity is related to the presence of sAPPa. Importantly, it indicates that the mechanism of action of exogenously added sAPPa is independent of the presence of endogenous APP.