Age At Injury And Genotype Modify Acute Inflammatory And Neurofilament-light Responses To Mild Chimera Traumatic Brain Injury In Wild-type And App/ps1 Mice
W Hang Cheng, S Stukas, K Martens, C Wellington et. al.
Peak incidence of traumatic brain injury (TBI) occurs in both young and old individuals, and older age at injury is associated with worse outcome and poorer recovery. Moderate-severe TBI is a reported risk factor for dementia, including Alzheimer’s disease (AD), but whether mild TBI (mTBI) alters AD pathogenesis is not clear. To delineate how age at injury and predisposition to amyloid formation affect the acute response to mTBI, we used the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of TBI to induce two mild injuries in wild-type (WT) and APP/PS1 mice at either 6 or 13 months of age and assessed behavioural, histological and biochemical changes up to 14 days post-injury. Age at injury did not alter acute behavioural responses to mTBI, including measures of neurological status, motor performance, spatial memory, fear, or anxiety, in either strain. Young APP/PS1 mice showed a subtle and transient increase in diffuse Aβ deposits after injury, whereas old APP/PS1 mice showed decreased amyloid deposits, without significant alterations in total soluble or insoluble Aβ levels at either age. Age at injury and genotype showed complex responses with respect to microglial and cytokine outcomes, where post-injury neuroinflammation is increased in old WT mice but attenuated in old APP/PS1 mice. Intriguingly, silver staining confirmed axonal damage in both strains and ages, yet only young WT and APP/PS1 mice showed neurofilament-positive axonal swellings after mTBI, as this response was almost entirely attenuated in old mice. Plasma neurofilament-light levels were significantly elevated after injury only in young APP/PS1 mice. This study suggests that mild TBI has minimal effects on Aβ metabolism, but that age and genotype can each modify acute outcomes related to white matter injury.