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.