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Isolated mitochondria from brain or cortical neurons of transgenic mice overexpressing SREBP-2 (<jats:italic>sterol regulatory element binding protein 2<\/jats:italic>) or NPC1 (<jats:italic>Niemann-Pick type C1<\/jats:italic>) knock-out mice exhibited mitochondrial cholesterol accumulation, mitochondrial glutathione (mGSH) depletion and increased susceptibility to A\u03b21\u201342-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 A\u03b21\u201342-mediated cell death. Intracerebroventricular human A\u03b2 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 A\u03b2 toxicity via mGSH regulation; strategies boosting the particular pool of mGSH may be of relevance to slow down disease progression.<\/jats:p>","DOI":"10.1523\/jneurosci.4909-08.2009","type":"journal-article","created":{"date-parts":[[2009,5,20]],"date-time":"2009-05-20T17:40:29Z","timestamp":1242841229000},"page":"6394-6405","source":"Crossref","is-referenced-by-count":140,"title":["Mitochondrial Cholesterol Loading Exacerbates Amyloid \u03b2 Peptide-Induced Inflammation and Neurotoxicity"],"prefix":"10.1523","volume":"29","author":[{"given":"Anna","family":"Fern\u00e1ndez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Llacuna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 C.","family":"Fern\u00e1ndez-Checa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Colell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2009,5,20]]},"reference":[{"key":"2023041303381875000_29.20.6394.1","doi-asserted-by":"publisher","DOI":"10.1097\/JGP.0b013e31816b72d4"},{"key":"2023041303381875000_29.20.6394.2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R800007-JLR200"},{"key":"2023041303381875000_29.20.6394.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0600134103"},{"key":"2023041303381875000_29.20.6394.4","doi-asserted-by":"crossref","unstructured":"Bandaru VV Troncoso J Wheeler D Pletnikova O Wang J Conant K Haughey NJ (2007) ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain. 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