Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity.
The role of cholesterol in Alzheimer's disease (AD) has been linked to the generation of toxic amyloid beta peptides (Abeta). Using genetic mouse models of cholesterol loading, we examined whether mitochondrial cholesterol regulates Abeta neurotoxicity and AD pathology. Isolated mitochondria from brain or cortical neurons of transgenic mice overexpressing SREBP-2 (sterol regulatory element binding protein 2) or NPC1 (Niemann-Pick type C1) knock-out mice exhibited mitochondrial cholesterol accumulation, mitochondrial glutathione (mGSH) depletion and increased susceptibility to Abeta1-42-induced oxidative stress and release of apoptogenic proteins. Similar findings were observed in pharmacologically GSH-restricted rat brain mitochondria, while selective mGSH depletion sensitized human neuronal and glial cell lines to Abeta1-42-mediated cell death. Intracerebroventricular human Abeta delivery colocalized with mitochondria resulting in oxidative stress, neuroinflammation and neuronal damage that were enhanced in Tg-SREBP-2 mice and prevented upon mGSH recovery by GSH ethyl ester coinfusion, with a similar protection observed by intraperitoneal administration of GSH ethyl ester. Finally, APP/PS1 (amyloid precursor protein/presenilin 1) mice, a transgenic AD mouse model, exhibited mitochondrial cholesterol loading and mGSH depletion. Thus, mitochondrial cholesterol accumulation emerges as a novel pathogenic factor in AD by modulating Abeta toxicity via mGSH regulation; strategies boosting the particular pool of mGSH may be of relevance to slow down disease progression.
Fernández
Anna
A
Department of Cell Death and Proliferation, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas and Unidad de Hepatología, Hospital Clinic i Provincial, 08036 Barcelona, Spain.
Llacuna
Laura
L
Fernández-Checa
José C
JC
Colell
Anna
A
D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000648:ultrastructure; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D000077296:Niemann-Pick C1 Protein; D010446:Peptide Fragments / Q000633:toxicity*; D053764:Presenilin-1 / Q000235:genetics; D011506:Proteins / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D010446:Peptide Fragments; D053764:Presenilin-1; D011506:Proteins; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C075222:amyloid beta-protein (1-42); C042431:S-ethyl glutathione; D002784:Cholesterol; D005978:Glutathione