Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer's-prone mice after mTBI

Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer's disease (AD). Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI. We found that brain injury does not affect cognitive performance in APP-SWE mice. However, we detected an increase of key hallmarks of AD, including Aβ levels and BACE1 expression, in the cortices of traumatized transgenic mice. Moreover, significant changes in the expanded endocannabinoid (eCB) system, or endocannabinoidome (eCBome), occurred, including increased levels of the endocannabinoid 2-AG in APP-SWE mice in both the cortex and hippocampus, and N-acylserotonins, detected for the first time in the brain. The gene expression of enzymes for the biosynthesis and inactivation of eCBs and eCB-like mediators, and some of their main molecular targets, also underwent significant changes. We also identified the formation of heteromers between cannabinoid 1 (CB ) and serotonergic 2A (5HT ) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma. Mild TBI induces biochemical changes in AD genetically predisposed mice and the eCBome may play a role in the pathogenetic link between brain injury and neurodegenerative disorders also by interacting with the serotonergic system.