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This study examined how closed-head injury affects glucose metabolism in mice genetically modified to model Alzheimer's disease. Using isotope-labeled glucose tracers, researchers found that the most significant metabolic changes occurred 8 months after injury, with disrupted glucose processing at the pyruvate-lactate conversion point in both cortex and hippocampus, rather than in the later-stage energy-producing TCA cycle. The findings reveal a delayed, region-specific metabolic dysfunction following traumatic brain injury in an Alzheimer's disease model.
Why it matters
The delayed metabolic disruption identified in this study could help explain the mechanistic link between traumatic brain injury and increased Alzheimer's disease risk. Understanding these specific metabolic defects may guide development of targeted therapeutic interventions for TBI patients at risk of neurodegenerative disease.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Traumatic brain injury (TBI) is a risk factor for Alzheimer’s disease (AD), and both conditions are associated with impaired glucose metabolism and mitochondrial dysfunction. We previously reported time-dependent mitochondrial dysfunction following closed-head injury (CHI) in amyloid precursor protein/presenilin 1 (APP/PS1) knock-in (KI) mice, but whether glucose-derived carbon labeling showed a corresponding temporal pattern remained unknown. We hypothesized that early deficits would involve tricarboxylic acid (TCA)-cycle metabolites, whereas chronic changes persisted upstream at the pyruvate-lactate branchpoint. Here, oral uniformly 13C-labeled glucose ([U-13C]-glucose) tracing and gas chromatography-mass spectrometry (GC-MS)-based isotopologue analysis were used to quantify first-turn glucose-derived carbon fate in cortex and hippocampus. To distinguish the effects of age at injury from those of post-injury interval, mice were analyzed 1 month after injury either at 7 or 12 months of age or 8 months after injury at 12 months of age. The most pronounced alterations occurred 8 months after CHI, when KI mice exhibited increased pyruvate and lactate labeling in the cortex and broader increases in glycolytic labeling in the hippocampus. These findings suggest that in APP/PS1 KI mice, chronic closed-head injury produced a delayed shift in glucose-derived carbon labeling centered on glycolytic and pyruvate/lactate nodes, with loss of hippocampal precursor-product coupling but without broad reduction of first-turn TCA-linked labeling.