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Membrane-Modulating Drugs can Affect the Size of Amyloid-?25-35 Aggregates in Anionic Membranes.

ABSTRACT: The formation of amyloid-? plaques is one of the hallmarks of Alzheimer's disease. The presence of an amphiphatic cell membrane can accelerate the formation of amyloid-? aggregates, making it a potential druggable target to delay the progression of Alzheimer's disease. We have prepared unsaturated anionic membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) and added the trans-membrane segment A?25-35. Peptide plaques spontaneously form in these membranes at high peptide concentrations of 20?mol%, which show the characteristic cross-? motif (concentrations are relative to the number of membrane lipids and indicate the peptide-to-lipid ratio). We used atomic force microscopy, fluorescence microscopy, x-ray microscopy, x-ray diffraction, UV-vis spectroscopy and Molecular Dynamics (MD) simulations to study three membrane-active molecules which have been speculated to have an effect in Alzheimer's disease: melatonin, acetylsalicyclic acid (ASA) and curcumin at concentrations of 5?mol% (drug-to-peptide ratio). Melatonin did not change the structural parameters of the membranes and did not impact the size or extent of peptide clusters. While ASA led to a membrane thickening and stiffening, curcumin made membranes softer and thinner. As a result, ASA was found to lead to the formation of larger peptide aggregates, whereas curcumin reduced the volume fraction of cross-? sheets by ~70%. We speculate that the interface between membrane and peptide cluster becomes less favorable in thick and stiff membranes, which favors the formation of larger aggregates, while the corresponding energy mismatch is reduced in soft and thin membranes. Our results present evidence that cross-? sheets of A?25-35 in anionic unsaturated lipid membranes can be re-dissolved by changing membrane properties to reduce domain mismatch.

SUBMITTER: Khondker A

PROVIDER: S-EPMC6098001 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Membrane-Modulating Drugs can Affect the Size of Amyloid-β<sub>25-35</sub> Aggregates in Anionic Membranes.

Khondker Adree A Alsop Richard J RJ Himbert Sebastian S Tang Jennifer J Shi An-Chang AC Hitchcock Adam P AP Rheinstädter Maikel C MC

Scientific reports 20180817 1

The formation of amyloid-β plaques is one of the hallmarks of Alzheimer's disease. The presence of an amphiphatic cell membrane can accelerate the formation of amyloid-β aggregates, making it a potential druggable target to delay the progression of Alzheimer's disease. We have prepared unsaturated anionic membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) and added the trans-membrane segment Aβ<sub>25-35</sub>. Pepti ...[more]

PMID: 30120270

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Project description:During early stages of Alzheimer's disease (AD), synaptic dysfunction induced by toxic amyloid-β (Aβ) is present before the accumulation of histopathological hallmarks of the disease. This scenario produces impaired functioning of neuronal networks, altered patterns of synchronous activity and severe functional deficits mainly due to hyperexcitability of hippocampal networks. The molecular mechanisms underlying these alterations remain unclear but functional evidence, shown by our laboratory and others, points to the involvement of receptors/channels which modulate neuronal excitability, playing a pivotal role in early Aβ-induced AD pathogenesis. In particular, two potassium channels that control neuronal excitability, G protein-coupled activated inwardly-rectifying potassium channel (GirK), and voltage-gated K channel (KCNQ), have been recently linked to Aβ pathophysiology in the hippocampus. Specifically, by using Aβ25-35, we previously found that GirK conductance is greatly decreased in the hippocampus, and similar effects have also been reported on KCNQ conductance. Thus, in the present study, our goal was to determine the effect of Aβ on the transcriptional expression pattern of 17 genes encoding neurotransmitter receptors and associated channels which maintain excitatory-inhibitory neurotransmission balance in hippocampal circuits, with special focus in potassium channels. For this purpose, we designed a systematic and reliable procedure to analyze mRNA expression by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in hippocampal rat slices incubated with Aβ25-35. We found that: 1) Aβ down-regulated mRNA expression of ionotropic GluN1 and metabotropic mGlu1 glutamate receptor subunits as previously reported in other AD models; 2) Aβ also reduced gene expression levels of GirK2, 3, and 4 subunits, and KCNQ2 and 3 subunits, but did not change expression levels of its associated GABAB and M1 receptors, respectively. Our results provide evidence that Aβ can modulate the expression of these channels which could affect the hippocampal activity balance underlying learning and memory processes impaired in AD.

Dataset Information

Membrane-Modulating Drugs can Affect the Size of Amyloid-?25-35 Aggregates in Anionic Membranes.

Publications

Membrane-Modulating Drugs can Affect the Size of Amyloid-β<sub>25-35</sub> Aggregates in Anionic Membranes.

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