Traumatic brain injury exacerbates mitochondrial dysfunction in APP/PS1 knock-in mice through time-dependent...

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Neurodegenerative Diseases

Background:

• Cerebral hypometabolism is common in traumatic brain injury (TBI) and Alzheimer's disease (AD).
• Mechanisms underlying TBI- and AD-related hypometabolism, particularly their interplay, remain unclear.
• TBI impacts cerebral metabolism through blood-brain barrier damage and oxidative stress, while AD involves amyloid-β (Aβ) effects on mitochondria.

Purpose of the Study:

• To investigate if TBI-induced mitochondrial dysfunction exacerbates Aβ-mediated impairment in a mouse model.
• To explore the temporal relationship between TBI and AD pathology on mitochondrial function.
• To assess the influence of sex on vulnerability to combined TBI and AD insults.

Main Methods:

• Utilized a closed-head injury (CHI) model in APP/PS1 knock-in (KI) mice, a model for Alzheimer's disease.
• Administered CHI at 4-5 months of age, prior to endogenous plaque formation and mitochondrial deficits in KI mice.
• Assessed mitochondrial bioenergetics in hippocampal and cortical tissues at 1, 4, and 8 months post-injury using Seahorse assays.

Main Results:

• At 1 month post-injury, a genotype-by-injury interaction showed significantly greater mitochondrial dysfunction in KI mice compared to single insults, with males more affected than females.
• By 4-8 months post-injury, Aβ-mediated effects became dominant, and TBI-specific changes diminished, suggesting recovery or convergence on shared pathways.
• These findings indicate a temporary exacerbation of mitochondrial dysfunction by TBI in the context of early amyloidosis, influenced by sex.

Conclusions:

• TBI can transiently worsen mitochondrial deficits associated with early-stage Alzheimer's disease pathology.
• Sex significantly influences vulnerability to the combined effects of TBI and amyloidosis.
• Understanding these interactions is crucial for neurodegenerative disease research, emphasizing the role of sex as a biological variable.