Alzheimer’s-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury

Rishi R. Agrawal, Delfina Larrea, Yimeng Xu, Lingyan Shi, Hylde Zirpoli, Leslie G. Cummins, Valentina Emmanuele, Donghui Song, Taekyung D. Yun, Frank P. Macaluso, Wei Min, Steven G. Kernie, Richard J. Deckelbaum, Estela Area-Gomez

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer’s disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-β as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes (“MAM” domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD. Graphical Abstract: [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)2219-2241
Number of pages23
JournalCellular and Molecular Neurobiology
Issue number5
StatePublished - Jul 2023


  • Alzheimer’s
  • Brain injury
  • Contact sites
  • Lipids
  • Mitochondria
  • Neurodegeneration

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology


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