Interaction of Alzheimer’s β-Amyloid Peptides with Cholesterol: Mechanistic Insights into Amyloid Pore Formation

Scala, Coralie Di; Chahinian, Henri; Yahi, Nouara; Garmy, Nicolas; Fantini, Jacques

doi:10.1021/bi500373k

Cited by 140 publications

(203 citation statements)

References 156 publications

(321 reference statements)

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“…The hypotheses associated with the possible role of cholesterol in the pathogenesis of AD suggest that cholesterol may trigger the synthesis of AB peptide from amyloid precursor protein or increase amyloid plaque formation by lowering the aggregation threshold of AB peptide [44][45][46][47][48][49][50]. Based on our data it may be also suggested that cholesterol could play a key role in AB toxicity as a precursor molecule of steroid hormones.…”

Section: Discussionsupporting

confidence: 55%

“…Studies in recent years have addressed cholesterol, AB peptides and mitochondria as a dangerous trio for AD [39,45,47,75]. The hypotheses associated with the possible role of cholesterol in the pathogenesis of AD suggest that cholesterol may trigger the synthesis of AB peptide from amyloid precursor protein or increase amyloid plaque formation by lowering the aggregation threshold of AB peptide [44][45][46][47][48][49][50].…”

Section: Discussionmentioning

confidence: 99%

“…The hypotheses associated with the possible role of cholesterol in AB toxicity may be categorized in two groups. One group suggests that cholesterol can trigger the synthesis of AB peptide from amyloid precursor protein; the others claim that cholesterol may increase amyloid plaque formation by lowering the aggregation threshold of the AB peptide [44][45][46][47][48][49][50]. In contrast to existing hypotheses, it may be suggested that the changes in P and PS levels in the presence of AB and cholesterol may affect cell survival.…”

Section: Introduction and Aimmentioning

confidence: 99%

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Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol

et al. 2016

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Increased amyloid beta (AB) peptide concentration is one of the initiating factors in the neurodegeneration process. It has been suggested that cholesterol induces the synthesis of AB peptide from amyloid precursor protein or facilitates the formation of amyloid plaque by lowering the aggregation threshold of the peptide. It is also shown that AB peptides may affect cholesterol metabolism and the synthesis of steroid hormones such as progesterone and estradiol. Pregnenolone (P) and pregnenolone sulfate (PS) are the major steroids produced from cholesterol in neural tissue. In toxicity conditions, the effect of AB peptides on P and PS levels has not yet been determined. Furthermore, it has not been clearly defined how changes in cellular P and PS levels affect neuronal cell survival. The aim of this study was to determine the effects of AB peptides on cellular changes in P and PS levels depending on the level of their main precursor, cholesterol. Cholesterol and toxic concentrations of AB fragments (AB 25-35, AB 1-40 and AB 1-42) were applied to PC-12 and SH-SY5Y cells. Changes in cellular cholesterol, P and PS levels were determined simultaneously in a dose-and time-dependent manner. The cell viability and cell death types were also evaluated. AB peptides affected both cell viability and P/PS levels. Steroid levels were altered depending on AB fragment type and the cholesterol content of the cells. Treatment with each of the AB fragments alone increased P levels by twofold. However, combined treatment with AB peptides and cholesterol increased P levels by approximately sixfold, while PS levels were increased only about 2.5 fold in both cell lines. P levels in the groups treated with AB 25-35 were higher than those in AB 1-40 and AB 1-42 groups. The cell viabilities were significantly low in the group treated by AB and cholesterol (9 mM). The effect of AB peptides on P levels might be a result of cellular self-defense. On the other hand, the rate of P increase might be playing a key role in the cell death mechanism of AB toxicity depending on cellular cholesterol levels.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introduction and Aimmentioning

confidence: 99%

See 1 more Smart Citation

Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol

et al. 2016

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“…In silico models of oligomeric Aβ(1-40) and Aβ(1-42) have suggested the formation of an acidic central pore involving Glu3, Asp7 and Glu11 (Diaz et al 2006 ). A tetrameric channel was proposed as a model for oligomeric Aβ(1-42) bound to cholesterol in the membrane (Di Scala et al 2014a ).…”

Section: Aβ Toxicity and Perturbation Of Cell Membranesmentioning

confidence: 99%

Lipids in Amyloid-β Processing, Aggregation, and Toxicity

Morgado

Garvey

2015

Advances in Experimental Medicine and Biology

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Aggregation of amyloid-beta (Aβ) peptide is the major event underlying neuronal damage in Alzheimer's disease (AD). Specific lipids and their homeostasis play important roles in this and other neurodegenerative disorders. The complex interplay between the lipids and the generation, clearance or deposition of Aβ has been intensively investigated and is reviewed in this chapter. Membrane lipids can have an important influence on the biogenesis of Aβ from its precursor protein. In particular, increased cholesterol in the plasma membrane augments Aβ generation and shows a strong positive correlation with AD progression. Furthermore, apolipoprotein E, which transports cholesterol in the cerebrospinal fluid and is known to interact with Aβ or compete with it for the lipoprotein receptor binding, significantly influences Aβ clearance in an isoform-specific manner and is the major genetic risk factor for AD. Aβ is an amphiphilic peptide that interacts with various lipids, proteins and their assemblies, which can lead to variation in Aβ aggregation in vitro and in vivo. Upon interaction with the lipid raft components, such as cholesterol, gangliosides and phospholipids, Aβ can aggregate on the cell membrane and thereby disrupt it, perhaps by forming channel-like pores. This leads to perturbed cellular calcium homeostasis, suggesting that Aβ-lipid interactions at the cell membrane probably trigger the neurotoxic cascade in AD. Here, we overview the roles of specific lipids, lipid assemblies and apolipoprotein E in Aβ processing, clearance and aggregation, and discuss the contribution of these factors to the neurotoxicity in AD.

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“…This 418 might be related to the processive cleavage by the γ-secretase, as flexi-419 bility allows the helix to adopt to the sluice-like active site of the prote-420 ase[146][147][148][149]. Importantly, the proteolytic efficiency is enhanced 2-4 421 fold in the presence of cholesterol[150].422In recent studies a cholesterol-binding site and a homodimerization 423 interface at C99 were defined[146,[151][152][153]. Homodimerization and 424 cholesterol binding were found to compete, as both involve the glycine 425 zipper motif G 700 xxxG 704 xxxG 708 G 709[151] (Fig.…”

mentioning

confidence: 99%

Functional competition within a membrane: Lipid recognition vs. transmembrane helix oligomerization

Stangl

Schneider

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Binding of specific lipids to large, polytopic membrane proteins is well described, and it is clear that such lipids are crucial for protein stability and activity. In contrast, binding of defined lipid species to individual transmembrane helices and regulation of transmembrane helix monomer-oligomer equilibria by binding of distinct lipids is a concept, which has emerged only lately. Lipids bind to single-span membrane proteins, both in the juxta-membrane region as well as in the hydrophobic membrane core. While some interactions counteract transmembrane helix oligomerization, in other cases lipid binding appears to enhance oligomerization. As reversible oligomerization is involved in activation of many membrane proteins, binding of defined lipids to single-span transmembrane proteins might be a mechanism to regulate and/or fine-tune the protein activity. But how could lipid binding trigger the activity of a protein? How can binding of a single lipid molecule to a transmembrane helix affect the structure of a transmembrane helix oligomer, and consequently its signaling state? These questions are discussed in the present article based on recent results obtained with simple, single-span transmembrane proteins. This article is part of a Special Issue entitled: Lipid-protein interactions.

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Interaction of Alzheimer’s β-Amyloid Peptides with Cholesterol: Mechanistic Insights into Amyloid Pore Formation

Cited by 140 publications

References 156 publications

Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol

Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol

Lipids in Amyloid-β Processing, Aggregation, and Toxicity

Functional competition within a membrane: Lipid recognition vs. transmembrane helix oligomerization

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