Cholesterol loss during glutamate-mediated excitotoxicity

Sodero, Alejandro Omar; Vriens, Joris; Ghosh, Debapriya; Stegner, David; Brachet, Anna; Pallotto, Marta; Sassoè‐Pognetto, Marco; Brouwers, Jos F.; Helms, J. Bernd; Nieswandt, Bernhard; Voets, Thomas; Dotti, Carlos G.

doi:10.1038/emboj.2012.31

Cited by 81 publications

(78 citation statements)

References 57 publications

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“…Endogenous 24S-HC may be elevated by excitatory synaptic transmission [27–29]. Hippocampal cultures exhibit age-related, activity-dependent cholesterol loss that involves reactive oxygen species, CYP46A1 mobilization [27, 28], and elevated 24S-HC in culture medium [29].…”

Section: Discussionmentioning

confidence: 99%

24S-hydroxycholesterol and 25-hydroxycholesterol differentially impact hippocampal neuronal survival following oxygen-glucose deprivation

et al. 2017

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N-methyl-D-aspartate receptors (NMDARs), a major subtype of glutamate receptor mediating excitatory transmission throughout the CNS, participate in ischemia-induced neuronal death. Unfortunately, undesired side effects have limited the strategy of inhibiting/blocking NMDARs as therapy. Targeting endogenous positive allosteric modulators of NMDAR function may offer a strategy with fewer downsides. Here, we explored whether 24S-hydroxycholesterol (24S-HC), an endogenous positive NMDAR modulator characterized recently by our group, participates in NMDAR-mediated excitotoxicity following oxygen-glucose deprivation (OGD) in primary neuron cultures. 24S-HC is the major brain cholesterol metabolite produced exclusively in neurons near sites of glutamate transmission. By selectively potentiating NMDAR current, 24S-HC may participate in NMDAR-mediated excitotoxicity following energy failure, thus impacting recovery after stroke. In support of this hypothesis, our findings indicate that exogenous application of 24S-HC exacerbates NMDAR-dependent excitotoxicity in primary neuron culture following OGD, an ischemic-like challenge. Similarly, enhancement of endogenous 24S-HC synthesis reduced survival rate. On the other hand, reducing endogenous 24S-HC synthesis alleviated OGD-induced cell death. We found that 25-HC, another oxysterol that antagonizes 24S-HC potentiation, partially rescued OGD-mediated cell death in the presence or absence of exogenous 24S-HC application, and 25-HC exhibited NMDAR-dependent/24S-HC-dependent neuroprotection, as well as NMDAR-independent neuroprotection in rat tissue but not mouse tissue. Our findings suggest that both endogenous and exogenous 24S-HC exacerbate OGD-induced damage via NMDAR activation, while 25-HC exhibits species dependent neuroprotection through both NMDAR-dependent and independent mechanisms.

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Section: Discussionmentioning

confidence: 99%

24S-hydroxycholesterol and 25-hydroxycholesterol differentially impact hippocampal neuronal survival following oxygen-glucose deprivation

et al. 2017

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“…56 Changes in cholesterol pathways and in apoE expression have been also associated to NMDA-mediated excitotoxicity. [57][58][59] Of note, 24OHC is a potent and specific modulator of NMDA receptors. 60 Although cholesterol homeostasis has been reported to contribute to enhanced excitotoxicity in HD, 61 however, further studies are needed to address this relationship.…”

Section: Discussionmentioning

confidence: 99%

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

et al. 2014

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In the adult brain, neurons require local cholesterol production, which is supplied by astrocytes through apoE-containing lipoproteins. In Huntington's disease (HD), such cholesterol biosynthesis in the brain is severely reduced. Here we show that this defect, occurring in astrocytes, is detrimental for HD neurons. Astrocytes bearing the huntingtin protein containing increasing CAG repeats secreted less apoE-lipoprotein-bound cholesterol in the medium. Conditioned media from HD astrocytes and lipoprotein-depleted conditioned media from wild-type (wt) astrocytes were equally detrimental in a neurite outgrowth assay and did not support synaptic activity in HD neurons, compared with conditions of cholesterol supplementation or conditioned media from wt astrocytes. Molecular perturbation of cholesterol biosynthesis and efflux in astrocytes caused similarly altered astrocyteneuron cross talk, whereas enhancement of glial SREBP2 and ABCA1 function reversed the aspects of neuronal dysfunction in HD. These findings indicate that astrocyte-mediated cholesterol homeostasis could be a potential therapeutic target to ameliorate neuronal dysfunction in HD. Huntington's disease (HD) is an adult-onset neurodegenerative disorder characterized by cell loss mainly in the striatum and cortex. Its pathophysiology is linked to an expanded CAG repeat in the IT-15 gene, which leads to an elongated polyQ tract in huntingtin (HTT) protein. No disease-modifying treatment is available for HD and novel pathophysiological insights and therapeutic strategies are needed. 1 Lipids are vital to brain health and function. Accordingly, the brain has a local source of cholesterol, 2 and a breakdown of cholesterol synthesis causes brain malformations and impaired cognitive function. 3,4 Cholesterol metabolism is disrupted in HD 5,6 as revealed by transcriptional, biochemical, and mass spectrometry analyses in HD rodent models. 7,8 This dysregulation is linked to a specific action of mutant HTT on sterol-regulatory-element-binding proteins (SREBPs) and on its target genes, whose reduced transcription leads to lower brain cholesterol levels. 7 In HD humans, brain cholesterol homeostasis is affected since pre-symptomatic stages, as determined by measurement of the brain-specific cholesterol catabolite 24-S-hydroxy-cholesterol (24OHC). 9,10 However, it remains unclear how reduced brain cholesterol would become pathological for HD neurons.In adulthood, astrocytes produce cholesterol, which is secreted as a complex with apolipoprotein (apo) E lipoproteins and delivered to neurons. 11,12 Mutant HTT is expressed in glial cells, 13,14 and transgenic mice overexpressing mutant HTT in astrocytes show age-dependent neurological symptoms. 15,16 Additionally, primary astrocytes overexpressing full-length human mutant HTT show reduced mRNA levels of cholesterol biosynthetic genes, along with impaired cellular production and secretion of apoE. 8 Here we employed molecular and cellular tools to test the impact of cholesterol perturbation between astrocytes and neur...

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“…Acute cholesterol depletion by cyclodextrin treatment results in altered membrane properties that can affect synaptic transmission in Purkinje cells and wildtype hippocampal neurons [57,58]. On the other hand, Sodero and coworkers have suggested that a sudden rise in excitatory neurotransmission activate CYP46A1-dependent mild cholesterol loss mechanisms to protect themselves from neuronal death [59]. Since CYP46A1 activity produces 24OHC, one may speculate that the CYP46A1-sGTPases-LXR axis in neurons is an additional layer of the cell's cholesterol quality control, impairing cholesterol reduction to levels that may affect synaptic transmission.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

et al. 2014

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The neuronal-specific cholesterol 24S-hydroxylase (CYP46A1) is important for brain cholesterol elimination. Cyp46a1 null mice exhibit severe deficiencies in learning and hippocampal long-term potentiation, suggested to be caused by a decrease in isoprenoid intermediates of the mevalonate pathway. Conversely, transgenic mice overexpressing CYP46A1 show an improved cognitive function. These results raised the question of whether CYP46A1 expression can modulate the activity of proteins that are crucial for neuronal function, namely of isoprenylated small guanosine triphosphate-binding proteins (sGTPases). Our results show that CYP46A1 overexpression in SH-SY5Y neuroblastoma cells and in primary cultures of rat cortical neurons leads to an increase in 3-hydroxy-3-methyl-glutaryl-CoA reductase activity and to an overall increase in membrane levels of RhoA, Rac1, Cdc42 and Rab8. This increase is accompanied by a specific increase in RhoA activation. Interestingly, treatment with lovastatin or a geranylgeranyltransferase-I inhibitor abolished the CYP46A1 effect. The CYP46A1-mediated increase in sGTPases membrane abundance was confirmed in vivo, in membrane fractions obtained from transgenic mice overexpressing this enzyme. Moreover, CYP46A1 overexpression leads to a decrease in the liver X receptor (LXR) transcriptional activity and in the mRNA levels of ATPbinding cassette transporter 1, sub-family A, member 1 and apolipoprotein E. This effect was abolished by inhibition of prenylation or by co-transfection of a RhoA dominantnegative mutant. Our results suggest a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons increase isoprenoid synthesis and sGTPase prenylation. This leads to a reduction in LXR activity, and consequently to a decrease in the expression of LXR target genes.

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Cholesterol loss during glutamate-mediated excitotoxicity

Cited by 81 publications

References 57 publications

24S-hydroxycholesterol and 25-hydroxycholesterol differentially impact hippocampal neuronal survival following oxygen-glucose deprivation

24S-hydroxycholesterol and 25-hydroxycholesterol differentially impact hippocampal neuronal survival following oxygen-glucose deprivation

Disruption of astrocyte-neuron cholesterol cross talk affects neuronal function in Huntington’s disease

Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

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