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Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent
Elika Z Moallem1, Hemendra J Vekaria2, Teresa Macheda2
1Spinal Cord & Brain Injury Research Center, University of Kentucky, Lexington, KY, United States of America; Department of Neuroscience, University of Kentucky, Lexington, KY, United States of America; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States of America.
Experimental Neurology
|January 1, 2026
Summary
Traumatic brain injury (TBI) temporarily worsens mitochondrial dysfunction in Alzheimer
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Neurodegenerative Diseases
Background:
- Cerebral hypometabolism is a hallmark of both traumatic brain injury (TBI) and Alzheimer's disease (AD).
- Mechanisms underlying TBI- and AD-related hypometabolism, particularly their interplay, remain incompletely understood.
- Mitochondrial dysfunction is implicated in both conditions, but its role in their combined effects is unclear.
Purpose of the Study:
- To investigate whether TBI exacerbates amyloid-β (Aβ)-mediated mitochondrial dysfunction in a mouse model of AD.
- To examine the temporal dynamics and sex-specific differences in the combined effects of TBI and AD pathology on cerebral metabolism.
Main Methods:
- Utilized a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice, a model for AD.
- Assessed mitochondrial bioenergetics in hippocampal and cortical tissues at 1, 4, and 8 months post-injury using Seahorse assays.
- Analyzed sex-specific vulnerability to TBI and AD-related mitochondrial dysfunction.
Main Results:
- At 1 month post-injury, a significant genotype-by-injury interaction showed exacerbated mitochondrial dysfunction in KI mice compared to single conditions, with males being more vulnerable.
- By 4-8 months post-injury, amyloid-mediated effects became predominant, and TBI-specific changes diminished, suggesting recovery or convergence on shared pathways.
- These findings highlight a temporary exacerbation of mitochondrial deficits by TBI in the context of early amyloidosis, influenced by sex.
Conclusions:
- TBI can transiently worsen mitochondrial dysfunction associated with early-stage Alzheimer's disease pathology.
- Sex is a critical biological variable influencing vulnerability to combined TBI and AD-related mitochondrial impairment.
- The study provides insights into the temporal relationship between TBI and amyloid-induced mitochondrial deficits, informing neurodegenerative disease research.
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