Upregulated functionality of mitochondria-associated ER membranes in a mouse model of traumatic brain injury

Abstract

AbstractTraumatic brain injury (TBI) is a major cause of death and disability in the United States. A history of TBI can lead to neurodegenerative diseases such as Alzheimer’s disease (AD) in a severity- and frequency-dependent manner. We previously reported that early stages of AD are characterized by alterations in lipid metabolism due to upregulated functionality of mitochondria-associated ER membranes (“MAM” domains of the ER), a cellular hub of lipid metabolic regulation. This can be caused by increased localization of amyloid precursor protein (APP)’s C-terminal fragment of 99 a.a. (C99) at MAM, which promotes cellular cholesterol uptake and trafficking to the ER. Through this mechanism, MAM-localized C99 can stimulate MAM functionality. In this study, we recapitulate these phenotypes in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, we observed increased phospholipid synthesis, sphingomyelinase activity and cholesterol esterification in the cortex and hippocampus 1, 3 and 7 days after injury. These responses were predominant in microglia, and coincided with increased levels of MAM-localized C99. Altogether, we propose that upregulation of MAM functionality could contribute, in part, to the epidemiological connection between TBI and AD.