Complex of Amyloid β Peptides with 24-Hydroxycholesterol and Its Effect on Hemicholinium-3 Sensitive Carriers

Krištofíková, Zdena; Kopecký, Vladimı́r; Hofbauerová, Kateřina; Hovorková, Petra; Řı́pová, Daniela

doi:10.1007/s11064-007-9443-5

Cited by 22 publications

(22 citation statements)

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“…However, it was not clear if the observed interactions between naturally occurring and brain originating 24(S)hydroxycholesterol (24(S)OH, known also as cerebrosterol) and Ab could be highly stereospecific (i.e., if they could reflect a possible physiological relevance) or if they could be rather nonspecific (which would be in agreement with our previous experiments showing the absence of marked differences in the interactions of non-aggregated or aggregated Ab with racemic 24-hydroxycholesterol see [25]). …”

Section: Introductionsupporting

confidence: 83%

“…Synaptosomes were prepared according to our previous study [25]. Briefly, the hippocampi were placed in ice-cold 0.32 M sucrose (10 ml/g tissue) and were homogenized with a glass-Teflon Potter's Braun homogenizer (10 upand down-strokes at 600 rpm).…”

Section: Preparations Of Undepleted or Cholesterol-depleted Synaptosomesmentioning

confidence: 99%

“…Although 10% DMSO does not prevent fibril formation, it stabilizes Ab upon subsequent dilution into buffers [32] and, moreover, it does not markedly affect high-affinity choline uptake values [25]. Fresh 5 lM solutions of Ab 1-40 were prepared in 10% DMSO, vigorously vortexed and immediately used.…”

Section: Stock Solutionsmentioning

confidence: 99%

“…In our previous study, we observed interactions between L-isoforms of Ab 1-40/1-42 and racemic 24-hydroxycholesterol by means of Raman spectroscopy and by means of an in vitro test based on increased vulnerability of presynaptically localized hemicholinium-3 (HC-3) sensitive choline carriers from rat hippocampal cholesterol-depleted synaptosomes to Ab or oxysterol actions [25]. However, it was not clear if the observed interactions between naturally occurring and brain originating 24(S)hydroxycholesterol (24(S)OH, known also as cerebrosterol) and Ab could be highly stereospecific (i.e., if they could reflect a possible physiological relevance) or if they could be rather nonspecific (which would be in agreement with our previous experiments showing the absence of marked differences in the interactions of non-aggregated or aggregated Ab with racemic 24-hydroxycholesterol see [25]).…”

Section: Introductionmentioning

confidence: 99%

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Interactions of Amyloid β Peptide 1–40 and Cerebrosterol

et al. 2011

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Amyloid β peptides appear to play a role in physiological processes; however, they are also involved in the pathogenesis of Alzheimer disease. Their actions under normal conditions are probably mediated by soluble monomeric L-isoforms at low concentrations, perhaps via highly specific interactions. On the contrary, toxic effects of aggregated natural L-isoforms/synthetic D-isoforms on membranes are very similar, but synthetic reverse/random L: -isoforms without pronounced aggregation properties are not toxic. Our previous work reported interactions of non-aggregated/aggregated L-isoforms of amyloid β peptides 1-40/1-42 with racemic 24-hydroxycholesterol. In this study, stereospecificity in the interactions of natural 24(S)hydroxycholesterol (cerebrosterol) or synthetic 24(R)hydroxycholesterol with soluble fragment 1-40 was evaluated by means of an in vitro test based on increased vulnerability of the hemicholinium-3 sensitive high-affinity choline uptake system in rat hippocampal cholesterol-depleted synaptosomes to the actions of amyloid β; computational simulations were also performed. Our results suggest that: (1) 24(S)hydroxycholesterol interacts with L-peptide 1-40 but not with the reverse L-peptide 40-1, (2) 24(R)hydroxycholesterol does not interact with L-peptide 1-40 or reverse 40-1, and (3) both enantiomers can probably interact with D-peptide 1-40. Therefore, the binding of 24(S)hydroxycholesterol is not fully stereospecific and the interaction could not reflect a physiological mechanism. Data from the computational simulation indicate that the hydrophobic core of the amyloid β molecule interacts with the hydrophobic part of 24(S)hydroxycholesterol, but no hydrogen bonds with high stability were found. Using this procedure, globular amyloid β could retain 24(S)hydroxycholesterol and thus contribute to its pathological accumulation in the brains of patients with Alzheimer disease.

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Section: Introductionsupporting

confidence: 83%

Section: Preparations Of Undepleted or Cholesterol-depleted Synaptosomesmentioning

confidence: 99%

Section: Stock Solutionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interactions of Amyloid β Peptide 1–40 and Cerebrosterol

et al. 2011

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“…Previous experiments on synaptosomes or cell cultures revealed that the disruption of lipid rafts using methyl-β-cyclodextrine treatment attenuated the HACU levels through a reduction in membrane-bound CHT1 and also through altered conformation. In addition, CHT1 from cholesterol-depleted synaptosomes appeared to be more vulnerable to Aβ actions [23,61]. Since perturbation of the lipid raft integrity are involved in AD pathogenesis [62], we suppose that the attenuated effects of some AChE inhibitors on CHT1 from cholesterol-depleted synaptic membranes (indicating, e.g., their stronger requirement to CHT1 conformation) should be advantageous with regard to AD therapy.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

Krištofiková¹,

Říčný²,

Soukup³

et al. 2016

Dement Geriatr Cogn Disord

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Background: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. Methods: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C₄-C₅ chains and 5 N-alkylated C₄-C₈ side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. Results: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. Conclusion: The N-alkylated derivative of 7-MEOTA bearing from C₄ side chains appears to be the most promising compound and should be evaluated in future in vivo research.

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Integrating Data for Modeling Biological Complexity

Hunter

Brayne

2014

Springer Handbook of Bio-/Neuroinformatics

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Complex of Amyloid β Peptides with 24-Hydroxycholesterol and Its Effect on Hemicholinium-3 Sensitive Carriers

Cited by 22 publications

References 47 publications

Interactions of Amyloid β Peptide 1–40 and Cerebrosterol

Interactions of Amyloid β Peptide 1–40 and Cerebrosterol

Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

Integrating Data for Modeling Biological Complexity

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