Unknown

Dataset Information

0

Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity.


ABSTRACT: 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.

SUBMITTER: Fernandez A 

PROVIDER: S-EPMC2740839 | biostudies-other | 2009 May

REPOSITORIES: biostudies-other

altmetric image

Publications

Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity.

Fernández Anna A   Llacuna Laura L   Fernández-Checa José C JC   Colell Anna A  

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090501 20


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 accumu  ...[more]

Similar Datasets

| S-EPMC5278219 | biostudies-literature
| S-EPMC8705864 | biostudies-literature
| S-EPMC4076561 | biostudies-literature
| S-EPMC6674660 | biostudies-literature
| S-EPMC3447396 | biostudies-literature
| S-EPMC3687350 | biostudies-literature
| S-EPMC8293670 | biostudies-literature
| S-EPMC5383535 | biostudies-literature
| S-EPMC7977450 | biostudies-literature
| S-EPMC6982359 | biostudies-literature