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.
- SourceAvailable from: Jan Albrecht
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- "Mitochondria isolated from cortical neurons of mice with enhanced cholesterol accumulation obtained by genetic manipulations: overexpression of SREBP-2, a sterol regulatory element binding protein 2 or Niemann–Pick type C1 knockout, showed a decrease in mGSH content and high susceptibility to Aβ-induced oxidative stress (Fernandez et al., 2009). In turn, selective mGSH depletion sensitized human neuronal and glial cell lines to Aβ-mediated cell death (Fernandez et al., 2009). Mitochondrial GSH depletion in SREBP-2-overexpressing APP/PS1 mice, an AD model, was shown to be subsequent to early mitochondrial cholesterol loading (Barbero-Camps et al., 2013). "
ABSTRACT: Oxidative and nitrosative stress (ONS) contributes to the pathogenesis of most brain maladies, and the magnitude of ONS is related to the ability of cellular antioxidants to neutralize the accumulating reactive oxygen and nitrogen species (ROS/RNS). While the major ROS/RNS scavengers and regenerators of bio-oxidized molecules: superoxide dysmutases (SODs), glutathione (GSH), thioredoxin (Trx) and peroxiredoxin (Prx) are distributed in all cellular compartments. This review specifically focuses on the role of the systems operating in mitochondria. There is a growing consensus that the mitochondrial SOD isoform - SOD2 and GSH are critical for the cellular antioxidant defense. Variable changes of the expression or activities of one or more of the mitochondrial antioxidant systems have been documented in the brains derived from human patients and/or in animal models of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebral ischemia, toxic brain cell damage associated with overexposure to mercury or excitotoxins, or hepatic encephalopathy. In many cases, ambiguity of the responses of the different antioxidant systems in one and the same disease need to be more conclusively evaluated before the balance of the changes in viewed as beneficial or detrimental. Modulation of the mitochondrial antioxidant systems may in the future become a target of antioxidant therapy. Copyright © 2014. Published by Elsevier Ltd.Neurochemistry International 01/2015; DOI:10.1016/j.neuint.2014.12.012 · 2.65 Impact Factor
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- "In some cases, the MCD-fed mice were co-treated with GSHee, NAC or necrostatin-1 to evaluate the course of liver damage induced by superoxide scavenging with MnTBAP. Lipid peroxidation was measured as the presence of carbonyl proteins determined by immunoblotting, as described before . In addition, in some cases, the MCD-fed mice were treated with the mitochondrial targeted antioxidant MitoQ or its inactive analogue decylTPP. "
ABSTRACT: Steatohepatitis (SH) is associated with mitochondrial dysfunction and excessive production of superoxide, which can then be converted into H(2)O(2) by SOD2. Since mitochondrial GSH (mGSH) plays a critical role in H(2)O(2) reduction, we explored the interplay between superoxide, H(2)O(2), and mGSH in nutritional and genetic models of SH, which exhibit mGSH depletion. We used isolated mitochondria and primary hepatocytes, as well as in vivo SH models showing mGSH depletion to test the consequences of superoxide scavenging. In isolated mitochondria and primary hepatocytes, superoxide scavenging by SOD mimetics or purified SOD decreased superoxide and peroxynitrite generation but increased H(2)O(2) following mGSH depletion, despite mitochondrial peroxiredoxin/thioredoxin defense. Selective mGSH depletion sensitized hepatocytes to cell death induced by SOD mimetics, and this was prevented by RIP1 kinase inhibition with necrostatin-1 or GSH repletion with GSH ethyl ester (GSHee). Mice fed the methionine-choline deficient (MCD) diet or MAT1A(-/-) mice exhibited reduced SOD2 activity; in vivo treatment with SOD mimetics increased liver damage, inflammation, and fibrosis, despite a decreased superoxide and 3-nitrotyrosine immunoreactivity, effects that were ameliorated by mGSH replenishment with GSHee, but not NAC. As a proof-of-principle of the detrimental role of superoxide scavenging when mGSH was depleted transgenic mice overexpressing SOD2 exhibited enhanced susceptibility to MCD-mediated SH. These findings underscore a critical role for mGSH in the therapeutic potential of superoxide scavenging in SH, and suggest that the combined approach of superoxide scavenging with mGSH replenishment may be important in SH.Journal of Hepatology 06/2012; 57(4):852-9. DOI:10.1016/j.jhep.2012.05.024 · 10.40 Impact Factor
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- "Brains of AD patients showed cholesterol accumulation specifically in Ab-immunopositive neurons (Ohm et al. 2003; Gómez-Ramos and Asuncion Moran 2007; Xiong et al. 2008). In brains of the AD mouse model APP/PS1, cholesterol accumulation was preceded by Ab accumulation (Fernández et al. 2009), indicating that Ab regulates cholesterol homeostasis and (or) trafficking. Ab, in particular Ab 42 internalized from the extracellular space, is resistant to cellular degradation, possibly dowing to the formation of protease-resistant aggregates (Knauer et al. 1992; Yang et al. 1995, 1999; Ditaranto et al. 2001). "
ABSTRACT: Since the discovery that apolipoprotein E, a cholesterol transport protein, is a major risk factor for Alzheimer's disease (AD) development, there has been a remarkable interest in understanding the many facets of the relationship between cholesterol and AD. Several lines of evidence have demonstrated the importance of cholesterol in amyloid beta peptide (Aβ) production and metabolism, as well as the involvement of Aβ in cholesterol homeostasis. The emerging picture is complex and still incomplete. This review discusses findings that indicate that a reciprocal regulation exists between Aβ and cholesterol at the subcellular level. The pathological impact of such regulation is highlighted.Canadian Journal of Physiology and Pharmacology 05/2012; 90(6):753-64. DOI:10.1139/y2012-076 · 1.55 Impact Factor