Alzheimer's-associated upregulation of mitochondria-associated ER membranes after traumatic brain injury
| Autor: | 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 |
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| Přispěvatelé: | Consejo Superior de Investigaciones Científicas (España), National Institutes of Health (US), Department of Defense (US), Agrawal, Rishi R., Larrea, Delfina, Zirpoli, Hylde, Cummins, Leslie G., Area-Gomez, Estela |
| Rok vydání: | 2020 |
| Předmět: |
Traumatic
Aging Hippocampus Neurodegenerative Mitochondrion Endoplasmic Reticulum Alzheimer's Disease Mice Amyloid beta-Protein Precursor Contact sites Amyloid precursor protein 2.1 Biological and endogenous factors Brain injury Aetiology Microglia biology Pharmacology and Pharmaceutical Sciences General Medicine Alzheimer's Lipids Mitochondria Up-Regulation medicine.anatomical_structure Neurological Alzheimer's disease medicine.medical_specialty Physical Injury - Accidents and Adverse Effects Traumatic brain injury 1.1 Normal biological development and functioning Traumatic Brain Injury (TBI) Cellular and Molecular Neuroscience Downregulation and upregulation Alzheimer Disease Underpinning research Internal medicine Acquired Cognitive Impairment medicine Animals Neurodegeneration Traumatic Head and Spine Injury Neurology & Neurosurgery business.industry Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Lipid metabolism Cell Biology medicine.disease Brain Disorders Endocrinology Brain Injuries biology.protein Dementia Biochemistry and Cell Biology business Alzheimer’s |
| Zdroj: | Cellular and molecular neurobiology, vol 43, iss 5 |
| DOI: | 10.1101/2020.11.13.381756 |
| Popis: | 23 p.-5 fig.-3 tab.-1 graph. abst. 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. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the U.S. National Institutes of Health (T32-DK007647 to RRA; R21NS125395 to LS; S10-OD016214 and P30-CA013330 to FPM; R01-EB029523 to WM; R01-NS095803 to SGK; R01-NS088197 to RJD; R01-AG056387 to EA-G) and the U.S. Department of Defense (National Defense Science and Engineering Graduate Fellowship, FA9550-11-C-0028, to RRA). |
| Databáze: | OpenAIRE |
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