Traumatic Brain Injury Alters the Trajectory of Age-Related Mitochondrial Change.

Abstract

Background:

Some epidemiologic studies associate traumatic brain injury (TBI) with Alzheimer's disease (AD).

Objective:

To test whether a TBI-induced acceleration of age-related mitochondrial change could potentially mediate the reported TBI-AD association.

Methods:

We administered unilateral controlled cortical impact (CCI) or sham injuries to 5-month-old C57BL/6J and tau transgenic rTg4510 mice. In the non-transgenics, we assessed behavior (1-5 days, 1 month, and 15 months), lesion size (1 and 15 months), respiratory chain enzymes (1 and 15 months), and mitochondrial DNA copy number (mtDNAcn) (1 and 15 months) after CCI/sham. In the transgenics we quantified post-injury mtDNAcn and tangle burden.

Results:

In the non-transgenics CCI caused acute behavioral deficits that improved or resolved by 1-month post-injury. Protein-normalized complex I and cytochrome oxidase activities were not significantly altered at 1 or 15 months, although complex I activity in the CCI ipsilesional cortex declined during that period. Hippocampal mtDNAcn was not altered by injury at 1 month, increased with age, and rose to the greatest extent in the CCI contralesional hippocampus. In the injured then aged transgenics, the ipsilesional hippocampus contained less mtDNA and fewer tangles than the contralesional hippocampus; mtDNAcn and tangle counts did not correlate.

Conclusions:

As mice age their brains increase mtDNAcn as part of a compensatory response that preserves mitochondrial function, and TBI enhances this response. TBI may, therefore, increase the amount of compensation required to preserve late-life mitochondrial function. If TBI does modify AD risk, altering the trajectory or biology of aging-related mitochondrial changes could mediate the effect.

• Authors: Janna L Harris, Xiaowan Wang, Sarah K Christian, Lesya Novikova, Anuradha Kalani, Dongwei Hui, Sadie Ferren, Scott Barbay, Judit Perez Ortiz, Randolph J Nudo, William M Brooks, Heather M Wilkins, Prabhakar Chalise, Mary Lou Michaelis, Elias K Michaelis, Russell H Swerdlow
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 97 Issue 4 Pg. 1793-1806 ( 2024) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 38306050 (Publication Type: Journal Article)

Chemical References

• DNA, Mitochondrial

Topics

• Mice
• Animals
• Mice, Inbred C57BL
• Brain Injuries, Traumatic (pathology)
• Brain (pathology)
• Mitochondria (pathology)
• DNA, Mitochondrial (genetics)
• Mice, Transgenic
• Alzheimer Disease
• Disease Models, Animal