The spirostenol (22R, 25R)-20α-spirost-5-en-3β-yl hexanoate blocks mitochondrial uptake of Aβ in neuronal cells and prevents Aβ-induced impairment of mitochondrial function

Tillement, Laurent; Lecanu, Laurent; Yao, Wenguo; Greeson, Janet; Papadopoulos, Vassilios

doi:10.1016/j.steroids.2006.05.003

Cited by 44 publications

(45 citation statements)

References 35 publications

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“…A resulting conclusion could be that even an additional supply of cholesterol to depleted brain cells is insufficient [60] . This is obviously a very promising pharmacological target: natural derivatives of spirostenols seem to be able to reproduce the effects of 22R-OH-cholesterol and are currently in development [72,73] .…”

Section: Normalization Of Cerebral Cholesterol Metabolismmentioning

confidence: 99%

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

Tillement¹,

Lecanu

Papadopoulos³

2009

Pharmacology

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Most neurodegenerative diseases share several clinical, genetic and pathophysiological features, and an irreversible evolution as well. They are characterized by an endogenous production of abnormal proteins called amyloid proteins (AP), which are not hydrosoluble, form depots, and are only partly cleared by autophagy and the ubiquitin-protease system. Despite their different structures, they are probably generated by a common pathological pathway, a misfolding process. This hypothesis suggests a common pharmacological approach, which can consist of either the blockade of the misfolding process, the elimination of AP or both. The currently validated treatments are mostly palliative ones, trying to supplant the function of destroyed neurons. New trends involve the regulation of the cerebral cholesterol metabolism and the preservation of neuron mitochondrial functions. Special attention is given to already marketed drugs used for other indications, which are also able to act on neurodegeneration.

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Section: Normalization Of Cerebral Cholesterol Metabolismmentioning

confidence: 99%

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

Tillement¹,

Lecanu

Papadopoulos³

2009

Pharmacology

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“…One mechanism underlying A ␤ neurotoxicity is mitochondrial dysfunction. The direct interaction between A ␤ and mitochondria was first shown in human neuroblastoma cells [3] . Using confocal microscopy, we demonstrated that incubation of cells with the A ␤ 1-42 fragment (A ␤ 1-42 ) resulted in co-localization of this peptide fragment with complex II of the mitochondrial respiratory chain.…”

Section: Introductionmentioning

confidence: 97%

“…Using confocal microscopy, we demonstrated that incubation of cells with the A ␤ 1-42 fragment (A ␤ 1-42 ) resulted in co-localization of this peptide fragment with complex II of the mitochondrial respiratory chain. This led us to hypothesize that A ␤ passed through both the cell membrane and the outer mitochondrial membrane [3] . These findings were confirmed by Hansson Petersen et al [4] , who showed that A ␤ is transported into mitochondria via the translocase of the outer membrane (TOM40) and the translocase of the inner membrane (TIM22).…”

Section: Introductionmentioning

confidence: 99%

“…A ␤ is not only transported into mitochondria, but also inhibits mitochondrial respiration [3] , likely affecting several proteins involved in this process. In support of this hypothesis, A ␤ has been shown to interact with the ␣ -subunit of ATP synthase, leading to ATP depletion [5] .…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, complex III appears to be one of the sites of superoxide radical production. As a result, the inhibition of mitochondrial respiration and depletion in ATP observed in AD may be accompanied by the deleterious effects of reactive oxygen species (ROS) [3] . We have also reported that complexes IV and V are targets of A ␤ in human neuroblastoma cells [3] .…”

Section: Introductionmentioning

confidence: 99%

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Further Evidence on Mitochondrial Targeting of β-Amyloid and Specificity of β-Amyloid-Induced Mitotoxicity in Neurons

Tillement

Lecanu²,

Papadopoulos³

2011

Neurodegener Dis

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Background/Aims: Impaired mitochondrial function has been described in Alzheimer’s disease. We previously reported that, in neuronal cells, β-amyloid 1–42 (Aβ_1–42) is targeted to mitochondria. We have also reported that, when incubated with isolated rat brain mitochondria, Aβ_1–42 inhibits complex IV, uncouples the mitochondrial respiratory chain, and promotes opening of the membrane permeability transition pore. Here, we further analyzed the targeting and mitotoxicity of Aβ_1–42. Methods and Results: Immunoelectron microscopy revealed that the mitochondrial targeting of Aβ_1–42 was concentration- and time-dependent. Incubation of human neuroblastoma cells with Aβ_1–42 increased the release of adenylate kinase, a mitochondrial enzyme released after membrane permeability transition pore opening. However, it failed to trigger DNA fragmentation and apoptosis, suggesting that the ability of this peptide to uncouple the respiratory chain underlies its mitotoxicity and cytotoxicity. Aβ_1–42 targeting to mitochondria was blocked by caprospinol, a steroid derivative shown to protect neuronal cells against Aβ_1–42-induced neurotoxicity. Further experiments revealed that the mitotoxic effect of Aβ_1–42 is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of Aβ_1–42 was not restricted to brain cells, indicating that it is not cell- or tissue-specific. Conclusion: Taken together, these results suggest that extracellular Aβ_1–42 targets neuronal mitochondria to exert its toxic effects.

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The Role of Oxidative Stress in Neurodegenerative Diseases

Książek-Winiarek

Głąbiński

2014

Oxidative Stress in Applied Basic Research and Clinical Practice

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The spirostenol (22R, 25R)-20α-spirost-5-en-3β-yl hexanoate blocks mitochondrial uptake of Aβ in neuronal cells and prevents Aβ-induced impairment of mitochondrial function

Cited by 44 publications

References 35 publications

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

Amyloidosis and Neurodegenerative Diseases: Current Treatments and New Pharmacological Options

Further Evidence on Mitochondrial Targeting of β-Amyloid and Specificity of β-Amyloid-Induced Mitotoxicity in Neurons

The Role of Oxidative Stress in Neurodegenerative Diseases

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