Abstract
Cerebral hypometabolism occurs in both traumatic brain injury (TBI) and Alzheimer's disease (AD), but whether these conditions act through distinct or overlapping mechanisms is unclear. TBI disrupts cerebral metabolism via blood–brain barrier damage, altered glucose transporter expression, calcium buffering abnormalities, and oxidative damage to metabolic enzymes. AD-related hypometabolism is linked to amyloid-β (Aβ) effects on mitochondria, including impaired respiration, oxidative stress, and altered mitophagy, fusion, and fission. We tested whether TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment using a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice. Injuries were delivered at 4–5 months of age, before plaque formation and mitochondrial deficits in KI mice. Bioenergetics were measured at 1, 4, and 8 months post-injury in hippocampus and cortex using Seahorse assays on isolated mitochondria. At 1 month, genotype-by-injury interactions revealed greater dysfunction in KI mice than either condition alone, with males more vulnerable than females. At 4–8 months, amyloid-mediated effects predominated, while TBI-specific changes were no longer apparent, suggesting recovery or convergence onto shared mechanisms. These results indicate that TBI can temporarily worsen mitochondrial dysfunction in the context of early amyloidosis, with sex influencing vulnerability. Findings provide insight into the temporal relationship between TBI and amyloid-induced mitochondrial deficits and support the importance of sex as a biological variable in neurodegenerative disease progression
Document Type
Article
Publication Date
2026
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.expneurol.2025.115629
Funding Information
This work was supported in part by the National Institutes of Health under award numbers RF1NS119165 (ADB) and T32AG078110 (EZM), the Kentucky Spinal and Head Injury Research Trust (Award 22-3 A, ADB), and the Department of Defense (Award AZ190017). This publication was also supported by the University of Kentucky Center for Neurotrauma and Metabolism (CNS-Met), which is supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number P20GM148326.
Repository Citation
Moallem, Elika Z.; Vekaria, Hemendra J.; Macheda, Teresa; Hawkins, Margaret R.; Roberts, Kelly N.; Patel, Samir P.; Sullivan, Patrick G.; and Bachstetter, Adam D., "Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent pathways" (2026). Spinal Cord and Brain Injury Research Center Faculty Publications. 42.
https://uknowledge.uky.edu/scobirc_facpub/42
Notes/Citation Information
0014-4886/© 2026 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).