Traumatic brain injury induces a sustained sensorimotor impairment associated with a dysregulated acute phase response in mice overexpressing human amyloid precursor protein.

Traumatic brain injury (TBI) significantly contributes to morbidity and mortality worldwide, often leading to cognitive decline. Although there is a recognised link between TBI and the acceleration of Alzheimer's disease (AD), the precise biological mechanisms driving this relationship are not fully understood. While several studies have investigated TBI in AD mouse models, none have examined the role of systemic inflammation in this context. In this study, we investigated the inflammatory responses, both centrally and peripherally, in 1-year-old wild-type (WT) and J20 mice (Tg:PDGFB-APPSwInd), overexpressing human amyloid precursor protein with the Swedish and Indiana mutations. Following controlled cortical impact (CCI) at 0.5 mm depth to the left somatosensory cortex, we examined outcomes at 1 and 7 days post-injury. The J20 mice exhibited a persistent sensorimotor impairment post-TBI, as determined by the adhesive removal test. Although amyloid-β42 deposition progressively increased post-injury, this behavioural deficit was not associated with greater neuronal loss compared to WT mice. Using qPCR, it was revealed that the level of proinflammatory cytokine and chemokine expression in the brain was largely conserved between WT and J20 mice, though brain Cxcl10 expression increased by 28.6 % in J20 mice at 7d-post injury compared to WT. However, J20 mice exhibited an exaggerated acute phase response (APR) to the TBI in the liver and spleen at 7d. Accompanying the potentiated APR, 1H NMR revealed that plasma glucose was decreased in J20 mice compared to WT at 7d. Taken together, this suggests that the sustained sensorimotor deficit in J20 mice is associated with increased amyloid-β pathology, and a dysregulated and prolonged systemic inflammatory response, accompanied by hypoglycaemia. In general, TBI in the presence of AD pathology, results in extended systemic inflammatory and metabolic responses that are likely to underpin the extended cognitive impairment, and our findings emphasise the need for customised interventions that address central and systemic inflammation after TBI in individuals with neurodegenerative disease.