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

Article type: Research Article

Authors: Harris, Janna L.^{a; b} | Wang, Xiaowan^a | Christian, Sarah K.^a | Novikova, Lesya^a | Kalani, Anuradha^a | Hui, Dongwei^a | Ferren, Sadie^a | Barbay, Scott^c | Ortiz, Judit Perez^a | Nudo, Randolph J.^c | Brooks, William M.^{a; d} | Wilkins, Heather M.^{a; d} | Chalise, Prabhakar^{a; e} | Michaelis, Mary Lou^a | Michaelis, Elias K. ^a | Swerdlow, Russell H.^{a; b; d; f; *}

Affiliations: [a] University of Kansas Alzheimer’s Disease Research Center, Kansas City, KS, USA | [b] Departments of Cell Biology and Physiology, University of Kansas Alzheimer’s Disease Research Center, The University of Kansas Medical Center, Kansas City, KS, USA | [c] Departments of Physical Medicine and Rehabilitation, University of Kansas Alzheimer’s Disease Research Center, The University of Kansas Medical Center, Kansas City, KS, USA | [d] Departments of Neurology, University of Kansas Alzheimer’s Disease Research Center, The University of Kansas Medical Center, Kansas City, KS, USA | [e] Departments of Biostatistics and Data Science, University of Kansas Alzheimer’s Disease Research Center, The University of Kansas Medical Center, Kansas City, KS, USA | [f] Departments of Biochemistry and Molecular Biology, University of Kansas Alzheimer’s Disease Research Center, The University of Kansas Medical Center, Kansas City, KS, USA

Correspondence: [*] Correspondence to: Russell H. Swerdlow, University of Kansas Alzheimer’s Disease Center, 4350 Shawnee Mission Parkway, Fairway, KS 66205, USA. Tel.: +1 913 588 0555; Fax: +1 913 588 0681; E-mail: rswerdlow@kumc.edu.

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.

Keywords: Aging, Alzheimer’s disease, brain, mitochondria, traumatic brain injury

DOI: 10.3233/JAD-231237

Journal: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1793-1806, 2024