Traumatic Brain Injury and Neurodegenerative Disease

McGuire, Dawn

doi:10.1002/9781118772034.ch26

Cited by 2 publications

(3 citation statements)

References 126 publications

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“…According to the Centers for Disease Control and Prevention (CDC), in 2014, 2.5 million people visited the emergency room due to a TBI, with 56,800 deaths and 80,000 patients developing long-term disabilities (statistics sourced from the Brain Trauma Foundation and the CDC). Patients often recover fully after single TBI episodes, but a history of multiple TBIs is correlated with increased vulnerability to neurodegenerative diseases such as Alzheimer's disease (AD) (Lye and Shores 2000;Van Den Heuvel et al 2007;McGuire 2018). Despite this epidemiological connection, the mechanism by which TBI can lead to AD-like neurodegeneration is unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Agrawal

Larrea

et al. 2022

Cell Mol Neurobiol

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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

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Section: Introductionmentioning

confidence: 99%

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

Agrawal

Larrea

et al. 2022

Cell Mol Neurobiol

View full text Add to dashboard Cite

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“…According to the CDC, 2.5 million people visited the emergency room following a TBI in 2014, with 56,800 deaths and approximately 80,000 of these patients developing long-term disabilities (statistics sourced from Brain Trauma Foundation and CDC). A large subset of these cases is characterized by the development of neurodegenerative diseases, especially in patients who have had multiple TBIs [1]. Even though these downstream consequences are usually grouped into a condition known as chronic traumatic encephalopathy (CTE) [2], a large percentage is clinically equivalent to Alzheimer's Disease (AD) [3].…”

Section: Introductionmentioning

confidence: 99%

“…According to the Centers for Disease Control and Prevention (CDC), in 2014, 2.5 million people visited the emergency room due to a TBI, with 56,800 deaths; approximately 80,000 of these patients developed long-term disabilities (statistics sourced from the Brain Trauma Foundation and the CDC). Patients often fully recover after single TBI episodes, but a history of multiple TBIs is correlated with increased vulnerability to neurodegenerative diseases such as Alzheimer disease (AD) (Lye and Shores 2000; Van Den Heuvel et al 2007; McGuire 2018). Despite this epidemiological connection, the mechanism by which TBI can lead to AD-like neurodegeneration is unknown.…”

Section: Introductionmentioning

confidence: 99%

Alzheimer's-associated upregulation of mitochondria-associated ER membranes after traumatic brain injury

Agrawal

Larrea

Shi

et al. 2020

Preprint

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Traumatic 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.

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Traumatic Brain Injury and Neurodegenerative Disease

Cited by 2 publications

References 126 publications

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

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

Alzheimer's-associated upregulation of mitochondria-associated ER membranes after traumatic brain injury

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