Brain Peroxisomes

Peroxisomes are essential organelles in higher eukaryotes as they play a major role in numerous metabolic pathways and redox homeostasis. Some peroxisomal abnormalities, which are often not compatible with life or normal development, were identified in severe demyelinating and neurodegenerative brain diseases. The metabolic roles of peroxisomes, especially in the brain, are described and human brain peroxisomal disorders resulting from a peroxisome biogenesis or a single peroxisomal enzyme defect are listed. The brain abnormalities encountered in these disorders (demyelination, oxidative stress, inflammation, cell death, neuronal migration, differentiation) are described and their pathogenesis are discussed. Finally, the contribution of peroxisomal dysfunctions to the alterations of brain functions during aging and to the development of Alzheimer's disease is considered

The oxysterol 27-hydroxycholesterol increases β-amyloid and oxidative stress in retinal pigment epithelial cells

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological features including β-amyloid (Aβ) peptide accumulation, oxidative damage, and cell death. The causes of AD and AMD are not known but several studies suggest disturbances in cholesterol metabolism as a culprit of these diseases. We have recently shown that the cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) causes AD-like pathology in human neuroblastoma SH-SY5Y cells and in organotypic hippocampal slices. However, the extent to which and the mechanisms by which 27-OHC may also cause pathological hallmarks related to AMD are ill-defined. In this study, the effects of 27-OHC on AMD-related pathology were determined in ARPE-19 cells. These cells have structural and functional properties relevant to retinal pigmented epithelial cells, a target in the course of AMD.</p> <p>Methods</p> <p>ARPE-19 cells were treated with 0, 10 or 25 μM 27-OHC for 24 hours. Levels of Aβ peptide, mitochondrial and endoplasmic reticulum (ER) stress markers, Ca²⁺homeostasis, glutathione depletion, reactive oxygen species (ROS) generation, inflammation and cell death were assessed using ELISA, Western blot, immunocytochemistry, and specific assays.</p> <p>Results</p> <p>27-OHC dose-dependently increased Aβ peptide production, increased levels of ER stress specific markers caspase 12 and gadd153 (also called CHOP), reduced mitochondrial membrane potential, triggered Ca²⁺dyshomeostasis, increased levels of the nuclear factor κB (NFκB) and heme-oxygenase 1 (HO-1), two proteins activated by oxidative stress. Additionally, 27-OHC caused glutathione depletion, ROS generation, inflammation and apoptotic-mediated cell death.</p> <p>Conclusions</p> <p>The cholesterol metabolite 27-OHC is toxic to RPE cells. The deleterious effects of this oxysterol ranged from Aβ accumulation to oxidative cell damage. Our results suggest that high levels of 27-OHC may represent a common pathogenic factor for both AMD and AD.</p

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

Oxysterols are 27-carbon atom molecules resulting from autoxidation or enzymatic oxidation of cholesterol. They are present in numerous foodstuffs and have been demonstrated to be present at increased levels in the plasma of patients with cardiovascular diseases and in atherosclerotic lesions. Thus, their role in lipid disorders is widely suspected, and they might also be involved in important degenerative diseases such as Alzheimer's disease, osteoporosis, and age-related macular degeneration. Since atherosclerosis is associated with the presence of apoptotic cells and with oxidative and inflammatory processes, the ability of some oxysterols, especially 7-ketocholesterol and 7&#946;-hydroxycholesterol, to trigger cell death, activate inflammation, and modulate lipid homeostasis is being extensively studied, especially in vitro. Thus, since there are a number of essential considerations regarding the physiological/pathophysiological functions and activities of the different oxysterols, it is important to determine their biological activities and identify their signaling pathways, when they are used either alone or as mixtures. Oxysterols may have cytotoxic, oxidative, and/or inflammatory effects, or none whatsoever. Moreover, a substantial accumulation of polar lipids in cytoplasmic multilamellar structures has been observed with cytotoxic oxysterols, suggesting that cytotoxic oxysterols are potent inducers of phospholipidosis. This basic knowledge about oxysterols contributes to a better understanding of the associated pathologies and may lead to new treatments and new drugs. Since oxysterols have a number of biological activities, and as oxysterol-induced cell death is assumed to take part in degenerative pathologies, the present review will focus on the cytotoxic activities of these compounds, the corresponding cell death signaling pathways, and associated events (oxidation, inflammation, and phospholipidosis)

Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7β-hydroxycholesterol on glioma cells

International audienceSteroidal maleic anhydrides were prepared in one step: lithocholic, chenodeoxicholic,deoxicholic, ursocholic, and hyodeoxicholic acid derivatives. Their capability to induce celldeath was studied on C6 rat glioma cells, and 7β-hydroxycholesterol was used as positivecytotoxic control. The highest cytotoxicity was observed with lithocholic andchenodeoxicholic acid derivatives (23-(4-methylfuran-2,5-dione)-3α-hydroxy-24-nor-5β-cholane (compound 1a), and 23-(4-methylfuran-2,5-dione)-3α,7α-dihydroxy-24-nor-5β-cholane (compound 1b), respectively), which induce a non-apoptotic mode of cell deathassociated with mitochondrial membrane potential loss and reactive oxygen speciesoverproduction. No cells with condensed and/or fragmented nuclei, no PARP degradation andno cleaved-caspase-3, which are apoptotic criteria, were observed. Similar effects were foundwith 7β-hydroxycholesterol. The cell clonogenic survival assay showed that compound 1bwas more cytotoxic than compound 1a and 7β-hydroxycholesterol. Compound 1b and 7β-hydroxycholesterol also induce cell cycle modifications. In addition, compounds 1a and 1b,and 7β-hydroxycholesterol favour the formation of large acidic vacuoles revealed by stainingwith acridine orange and monodansylcadaverine evocating autophagic vacuoles; they alsoinduce an increased ratio of [LC3-II / LC3-I], and modify the expression of mTOR, Beclin-1,Atg12, and Atg5-Atg12 which is are autophagic criteria. The ratio [LC3-II / LC3-I] is alsostrongly modified by bafilomycin acting on the autophagic flux. Rapamycin, an autophagicinducer, and 3-methyladenine, an autophagic inhibitor, reduce and increase 7β-hydroxycholesterol-induced cell death, respectively, supporting that 7β-hydroxycholesterolinduces survival autophagy. Alpha-tocopherol also strongly attenuates 7β-hydroxycholesterol-induced cell death. However, rapamycin, 3-methyladenine, and α-tocopherol have no effecton compounds 1a and 1b-induced cell death. It is concluded that these compounds trigger anon apoptotic mode of cell death, involving the mitochondria and associated with severalcharacteristics of autophagy