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

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Alzheimer Disease*/metabolism ; Alzheimer Disease*/genetics ; Mice, Transgenic* ; Endocannabinoids*/metabolism ; Cognitive Dysfunction*/metabolism; Animals ; Mice ; Serotonin/metabolism ; Biomarkers/metabolism ; Male ; Brain Concussion/metabolism ; Disease Models, Animal ; Mice, Inbred C57BL ; Brain/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Prodromal Symptoms ; Amyloid beta-Peptides/metabolism

Background: 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).
Methods: 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.
Results: 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 1-42 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 1 ) and serotonergic 2A (5HT 2A ) receptors, whose levels increased in the cortex of APP-SWE mTBI mice, possibly contributing to the exacerbated pathophysiology of AD induced by the trauma.
Conclusions: 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.
(© 2024. The Author(s).)

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W81XWH1810000 Peer Reviewed Alzheimer's Research Program

Keywords: APP-SWE mice; Alzheimer’s disease; Dementia; Endocannabinoidome; Serotonin; Traumatic brain injury

0 (Endocannabinoids)
333DO1RDJY (Serotonin)
0 (Biomarkers)
0 (Amyloid beta-Protein Precursor)
0 (Amyloid beta-Peptides)

Date Created: 20240711 Date Completed: 20240712 Latest Revision: 20240714

20240714

PMC11241935

10.1186/s40478-024-01820-0

38992700