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The Journal of Neuroscience, May 20, 2009, 29(20):6394-6405; doi:10.1523/JNEUROSCI.4909-08.2009

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Neurobiology of Disease
Mitochondrial Cholesterol Loading Exacerbates Amyloid β Peptide-Induced Inflammation and Neurotoxicity

Anna Fernández,^1,2,3,4 Laura Llacuna,^1,2,3,4 José C. Fernández-Checa,^1,2,3,4 * and Anna Colell^1,2,3,4 *

¹Department of Cell Death and Proliferation, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas and Unidad de Hepatología, Hospital Clinic i Provincial, ²Centro de Investigaciones Biomédicas Esther Koplowitz, ³Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, and ⁴Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Barcelona, Spain

Correspondence should be addressed to either Anna Colell or Jose C. Fernández-Checa, Department of Cell Death and Proliferation, Institut d'Investigacions Biomèdiques de Barcelona, Rosselló 161, 08036 Barcelona, Spain, Email: anna.colell{at}iibb.csic.es or Email: checa229{at}yahoo.com

The role of cholesterol in Alzheimer's disease (AD) has been linked to the generation of toxic amyloid β peptides (Aβ). Using genetic mouse models of cholesterol loading, we examined whether mitochondrial cholesterol regulates Aβ 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 Aβ1–42-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 Aβ1–42-mediated cell death. Intracerebroventricular human Aβ 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 Aβ toxicity via mGSH regulation; strategies boosting the particular pool of mGSH may be of relevance to slow down disease progression.

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Received Oct. 12, 2008; revised Feb. 5, 2009; accepted March 19, 2009.

Correspondence should be addressed to either Anna Colell or Jose C. Fernández-Checa, Department of Cell Death and Proliferation, Institut d'Investigacions Biomèdiques de Barcelona, Rosselló 161, 08036 Barcelona, Spain, Email: anna.colell{at}iibb.csic.es or Email: checa229{at}yahoo.com

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