Interaction of oxidative stress and neurotrauma in ALDH2−/− mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury
journal contributionposted on 2022-11-22, 22:56 authored by Rachel C Knopp, Sue H Lee, Michael Hollas, Emily Nepomuceno, David Gonzalez, Kevin Tam, Daniyal Aamir, Yueting Wang, Emily Pierce, Manel Ben AissaManel Ben Aissa, Gregory RJ Thatcher
Oxidative stress induced by lipid peroxidation products (LPP) accompanies aging and has been hypothesized to exacerbate the secondary cascade in traumatic brain injury (TBI). Increased oxidative stress is a contributor to loss of neural reserve that defines the ability to maintain healthy cognitive function despite the accumulation of neuropathology. ALDH2-/- mice are unable to clear aldehyde LPP by mitochondrial aldehyde dehydrogenase-2 (Aldh2) detoxification and provide a model to study mild TBI (mTBI), therapeutic interventions, and underlying mechanisms. The ALDH2-/- mouse model presents with elevated LPP-mediated protein modification, lowered levels of PSD-95, PGC1-α, and SOD-1, and mild cognitive deficits from 4 months of age. LPP scavengers are neuroprotective in vitro and in ALDH2-/- mice restore cognitive performance. A single-hit, closed skull mTBI failed to elicit significant effects in WT mice; however, ALDH2-/- mice showed a significant inflammatory cytokine surge in the ipsilateral hemisphere 24 h post-mTBI, and increased GFAP cleavage, a biomarker for TBI. Known neuroprotective agents, were able to reverse the effects of mTBI. This new preclinical model of mTBI, incorporating significant perturbations in behavior, inflammation, and clinically relevant biomarkers, allows mechanistic study of the interaction of LPP and neurotrauma in loss of neural reserve.
Center for Clinical and Translational Science Award U54 | Funder: National Institutes of Health (National Center for Advancing Translational Sciences) | Grant ID: UL1TR002003
Training Program in the Biology and Translational Research on Alzheimer's Disease and Related Dementias | Funder: National Institutes of Health (National Institute on Aging) | Grant ID: T32AG057468
CitationKnopp, R. C., Lee, S. H., Hollas, M., Nepomuceno, E., Gonzalez, D., Tam, K., Aamir, D., Wang, Y., Pierce, E., BenAissa, M.Thatcher, G. R. J. (2020). Interaction of oxidative stress and neurotrauma in ALDH2−/− mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury. Redox Biology, 32, 101486-. https://doi.org/10.1016/j.redox.2020.101486
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NeurosciencesInjury (total) Accidents/Adverse EffectsBrain DisordersInjury - Traumatic brain injuryInjury - Trauma - (Head and Spine)Behavioral and Social Science2.1 Biological and endogenous factorsMild traumatic brain injuryOxidative stressLipid peroxidationNeuroinflammationDrug discoveryAldehyde Dehydrogenase, MitochondrialAnimalsBrain ConcussionDisease Models, AnimalMiceNeuroprotective AgentsOxidative StressBiochemistry and Cell BiologyMedical Biochemistry and MetabolomicsPharmacology and Pharmaceutical Sciences