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

descriptionPublicationkeyboard_double_arrow_right Article 15 Nov 2020 Spain, United States, Spain Publisher:openRxivJournal:Cellular and Molecular Neurobiology, volume 43, pages 2,219-2,241 (issn: 0272-4340, eissn: 1573-6830,

Copyright policy )Funded by:NIH | Novel Optical Imaging App..., NIH | The role of ApoE in injur..., NIH | GRADUATE TRAINING IN NUTR... +5 projects

Authors: Rishi R. Agrawal; Delfina Larrea; Yimeng Xu; Lingyan Shi; Hylde Zirpoli; Leslie G. Cummins; Valentina Emmanuele; +7 Authors

doi: 10.1101/2020.11.13.381756 , 10.1007/s10571-022-01299-0

pmid: 36571634

pmc: PMC10287820

handle: 10261/286270

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

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Abstract

Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer 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-beta; as well as its precursor, 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 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.

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Spain, United States, Spain

Related Organizations

Yeshiva University
United States
California Digital Library
United States
University of California
United States
Centro de Investigaciones Biológicas
Spain
Albert Einstein College of Medicine
United States

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Keywords

Traumatic, Aging, Neurodegenerative, Acquired Cognitive Impairment (rcdc), Alzheimer's Disease, Endoplasmic Reticulum, Aging (rcdc), Contact sites, Mice, Amyloid beta-Protein Precursor, Brain Disorders (rcdc), Brain Injuries, Traumatic, Dementia (rcdc), 2.1 Biological and endogenous factors, Traumatic Brain Injury (TBI) (rcdc), Animals (mesh), Neurology & Neurosurgery (science-metrix), Brain injury, 3101 Biochemistry and cell biology (for-2020), Neurosciences (rcdc), Neurodegenerative (rcdc), Original Research, Alzheimer Disease (mesh), Alzheimer's Disease (rcdc), Mice (mesh), Pharmacology and Pharmaceutical Sciences, Biological Sciences, Physical Injury - Accidents and Adverse Effects (rcdc), Alzheimer's, 3209 Neurosciences (for-2020), Lipids, Mitochondria, Up-Regulation, Neurological, Endoplasmic Reticulum (mesh), 570, Physical Injury - Accidents and Adverse Effects, 1.1 Normal biological development and functioning, Mitochondria (mesh), 0601 Biochemistry and Cell Biology (for), 610, Amyloid beta-Protein Precursor (mesh), Traumatic Brain Injury (TBI), Alzheimer Disease, Acquired Cognitive Impairment, Animals, Neurodegeneration, Traumatic Head and Spine Injury, Traumatic Head and Spine Injury (rcdc), Up-Regulation (mesh), 1.1 Normal biological development and functioning (hrcs-rac), Neurology & Neurosurgery, 31 Biological Sciences (for-2020), 1115 Pharmacology and Pharmaceutical Sciences (for), Neurological (hrcs-hc), Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors (hrcs-rac), Lipids (mesh), 1109 Neurosciences (for), Brain Disorders, 3101 Biochemistry and Cell Biology (for-2020), Traumatic (mesh), Brain Injuries, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) (rcdc), Biochemistry and Cell Biology, Alzheimer’s

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