title: Endoplasmic reticulum stress mediates amyloid β neurotoxicity via mitochondrial cholesterol trafficking.
abstract: Disrupted cholesterol homeostasis has been reported in Alzheimer disease and is thought to contribute to disease progression by promoting amyloid β (Aβ) accumulation. In particular, mitochondrial cholesterol enrichment has been shown to sensitize to Aβ-induced neurotoxicity. However, the molecular mechanisms responsible for the increased cholesterol levels and its trafficking to mitochondria in Alzheimer disease remain poorly understood. Here, we show that endoplasmic reticulum (ER) stress triggered by Aβ promotes cholesterol synthesis and mitochondrial cholesterol influx, resulting in mitochondrial glutathione (mGSH) depletion in older age amyloid precursor protein/presenilin-1 (APP/PS1) mice. Mitochondrial cholesterol accumulation was associated with increased expression of mitochondrial-associated ER membrane proteins, which favor cholesterol translocation from ER to mitochondria along with specific cholesterol carriers, particularly the steroidogenic acute regulatory protein. In vivo treatment with the ER stress inhibitor 4-phenylbutyric acid prevented mitochondrial cholesterol loading and mGSH depletion, thereby protecting APP/PS1 mice against Aβ-induced neurotoxicity. Similar protection was observed with GSH ethyl ester administration, which replenishes mGSH without affecting the unfolded protein response, thus positioning mGSH depletion downstream of ER stress. Overall, these results indicate that Aβ-mediated ER stress and increased mitochondrial cholesterol trafficking contribute to the pathologic progression observed in old APP/PS1 mice, and that ER stress inhibitors may be explored as therapeutic agents for Alzheimer disease.
authors.affiliation: Department of Cell Death and Proliferation, Biomedical Research Institute of Barcelona - Higher Council for Scientific Research (IIBB-CSIC), Barcelona, Spain; Liver Unit, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), the Center for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Barbero-Camps
authors.affiliation: Department of Cell Death and Proliferation, Biomedical Research Institute of Barcelona - Higher Council for Scientific Research (IIBB-CSIC), Barcelona, Spain; Liver Unit, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), the Center for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain. Electronic address: josecarlos.fernandezcheca@iibb.csic.es.
authors.forename: Anna
authors.initials: A
authors.lastname: Fernández
authors.affiliation: Department of Cell Death and Proliferation, Biomedical Research Institute of Barcelona - Higher Council for Scientific Research (IIBB-CSIC), Barcelona, Spain; Liver Unit, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), the Center for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Baulies
authors.affiliation: Department of Cell Death and Proliferation, Biomedical Research Institute of Barcelona - Higher Council for Scientific Research (IIBB-CSIC), Barcelona, Spain; Liver Unit, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), the Center for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martinez
authors.affiliation: Department of Cell Death and Proliferation, Biomedical Research Institute of Barcelona - Higher Council for Scientific Research (IIBB-CSIC), Barcelona, Spain; Liver Unit, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), the Center for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain; Southern California Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address: checa229@yahoo.com.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Fernández-Checa
authors.affiliation: Department of Cell Death and Proliferation, Biomedical Research Institute of Barcelona - Higher Council for Scientific Research (IIBB-CSIC), Barcelona, Spain; Liver Unit, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), the Center for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain. Electronic address: anna.colell@iibb.csic.es.
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D005978:Glutathione