The interesting paper by Fernandez et al. (2009) reports that elevated cholesterol lowers brain mitochondrial glutathione (GSH), which, in turn, leads to increased oxidative vulnerability of mitochondria by Aβ42 in ex vivo experiments. In addition, the researchers added Aβ42 by ICV injection and report subsequent elevated indices of oxidative stress and inflammation. Glutathione ethyl ester co-infusion prevented these latter effects.
This paper is highly supportive of and consonant with our laboratory’s earlier papers that showed 1) injection of Aβ42 into rat basal forebrain led to oxidative damage in both the forebrain and hippocampus (Boyd-Kimball et al., 2005); 2) i.p. injection of a GSH mimetic, D609, protected subsequently isolated brain mitochondria from oxidative stress induced by Aβ42 (Ansari et al., 2006); 3) primary neuronal cultures were protected against Aβ42-induced oxidative damage by prior elevation of GSH (Boyd-Kimball et al., 2005); and 4) our proposal that elevation of brain levels of GSH could be a therapeutic approach for Alzheimer disease (Butterfield et al., 2002).
Cholesterol elevation, coupled to an oxidizing environment provided by Aβ42, could lead to elevation of cholesterol esters, which themselves become a source of oxidative stress. Oxidative stress itself, in addition to cholesterol elevation, can alter membrane fluidity with subsequent effects on membrane transporters (Sultana and Butterfield, 2008). Glutathione, as the source of reducing equivalents, is essential for the action of glutathione peroxidase (GPx), including GPx4 (which is resident in mitochondria). Scavenging of both hydrogen peroxide (formed in mitochondria by the action of MnSOD) and lipid hydroperoxides is a function of GPx; hence, depletion of mitochondrial GSH not only changes the redox potential of mitochondria, which could contribute to the authors’ finding of elevated apoptosis via opening of the mitochondrial permeability transition pore, but also decreased GSH could lead to elevated markers of oxidative stress.
This paper by Fernandez et al. underscores the view of our laboratory (Butterfield et al., 2001) and that of many others that Aβ42-mediated oxidative stress is a major contributor to the pathogenesis of Alzheimer disease. This current paper, coupled to our earlier papers, suggest that elevation of brain levels of GSH, particularly earlier in life, may be a promising therapeutic strategy to treat, slow, or possibly prevent many of the damaging effects of AD.
See also:
Butterfield DA, Pocernich CB, Drake J. Elevated Gutathione as a Therapeutic Strategy in Alzheimer's Disease. Drug Develop. Res.2002; 56, 428-437.
References:
Fernández A, Llacuna L, Fernández-Checa JC, Colell A.
Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity.
J Neurosci. 2009 May 20;29(20):6394-405.
PubMed.
Boyd-Kimball D, Sultana R, Poon HF, Lynn BC, Casamenti F, Pepeu G, Klein JB, Butterfield DA.
Proteomic identification of proteins specifically oxidized by intracerebral injection of amyloid beta-peptide (1-42) into rat brain: implications for Alzheimer's disease.
Neuroscience. 2005;132(2):313-24.
PubMed.
Ansari MA, Joshi G, Huang Q, Opii WO, Abdul HM, Sultana R, Butterfield DA.
In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer's disease and other oxidativ.
Free Radic Biol Med. 2006 Dec 1;41(11):1694-703. Epub 2006 Sep 8
PubMed.
Boyd-Kimball D, Sultana R, Abdul HM, Butterfield DA.
Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1-42)-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease.
J Neurosci Res. 2005 Mar 1;79(5):700-6.
PubMed.
Sultana R, Butterfield DA.
Alterations of some membrane transport proteins in Alzheimer's disease: role of amyloid beta-peptide.
Mol Biosyst. 2008 Jan;4(1):36-41.
PubMed.
Butterfield DA, Drake J, Pocernich C, Castegna A.
Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide.
Trends Mol Med. 2001 Dec;7(12):548-54.
PubMed.
Comments
University of Kentucky
The interesting paper by Fernandez et al. (2009) reports that elevated cholesterol lowers brain mitochondrial glutathione (GSH), which, in turn, leads to increased oxidative vulnerability of mitochondria by Aβ42 in ex vivo experiments. In addition, the researchers added Aβ42 by ICV injection and report subsequent elevated indices of oxidative stress and inflammation. Glutathione ethyl ester co-infusion prevented these latter effects.
This paper is highly supportive of and consonant with our laboratory’s earlier papers that showed 1) injection of Aβ42 into rat basal forebrain led to oxidative damage in both the forebrain and hippocampus (Boyd-Kimball et al., 2005); 2) i.p. injection of a GSH mimetic, D609, protected subsequently isolated brain mitochondria from oxidative stress induced by Aβ42 (Ansari et al., 2006); 3) primary neuronal cultures were protected against Aβ42-induced oxidative damage by prior elevation of GSH (Boyd-Kimball et al., 2005); and 4) our proposal that elevation of brain levels of GSH could be a therapeutic approach for Alzheimer disease (Butterfield et al., 2002).
Cholesterol elevation, coupled to an oxidizing environment provided by Aβ42, could lead to elevation of cholesterol esters, which themselves become a source of oxidative stress. Oxidative stress itself, in addition to cholesterol elevation, can alter membrane fluidity with subsequent effects on membrane transporters (Sultana and Butterfield, 2008). Glutathione, as the source of reducing equivalents, is essential for the action of glutathione peroxidase (GPx), including GPx4 (which is resident in mitochondria). Scavenging of both hydrogen peroxide (formed in mitochondria by the action of MnSOD) and lipid hydroperoxides is a function of GPx; hence, depletion of mitochondrial GSH not only changes the redox potential of mitochondria, which could contribute to the authors’ finding of elevated apoptosis via opening of the mitochondrial permeability transition pore, but also decreased GSH could lead to elevated markers of oxidative stress.
This paper by Fernandez et al. underscores the view of our laboratory (Butterfield et al., 2001) and that of many others that Aβ42-mediated oxidative stress is a major contributor to the pathogenesis of Alzheimer disease. This current paper, coupled to our earlier papers, suggest that elevation of brain levels of GSH, particularly earlier in life, may be a promising therapeutic strategy to treat, slow, or possibly prevent many of the damaging effects of AD.
See also:
Butterfield DA, Pocernich CB, Drake J. Elevated Gutathione as a Therapeutic Strategy in Alzheimer's Disease. Drug Develop. Res.2002; 56, 428-437.
References:
Fernández A, Llacuna L, Fernández-Checa JC, Colell A. Mitochondrial cholesterol loading exacerbates amyloid beta peptide-induced inflammation and neurotoxicity. J Neurosci. 2009 May 20;29(20):6394-405. PubMed.
Boyd-Kimball D, Sultana R, Poon HF, Lynn BC, Casamenti F, Pepeu G, Klein JB, Butterfield DA. Proteomic identification of proteins specifically oxidized by intracerebral injection of amyloid beta-peptide (1-42) into rat brain: implications for Alzheimer's disease. Neuroscience. 2005;132(2):313-24. PubMed.
Ansari MA, Joshi G, Huang Q, Opii WO, Abdul HM, Sultana R, Butterfield DA. In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer's disease and other oxidativ. Free Radic Biol Med. 2006 Dec 1;41(11):1694-703. Epub 2006 Sep 8 PubMed.
Boyd-Kimball D, Sultana R, Abdul HM, Butterfield DA. Gamma-glutamylcysteine ethyl ester-induced up-regulation of glutathione protects neurons against Abeta(1-42)-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. J Neurosci Res. 2005 Mar 1;79(5):700-6. PubMed.
Sultana R, Butterfield DA. Alterations of some membrane transport proteins in Alzheimer's disease: role of amyloid beta-peptide. Mol Biosyst. 2008 Jan;4(1):36-41. PubMed.
Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. Trends Mol Med. 2001 Dec;7(12):548-54. PubMed.
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