Project description:Sphingolipid signaling plays an important, yet not fully understood, role in diverse aspects of cellular life. Sphingomyelinase is a major enzyme in these signaling pathways, catalyzing hydrolysis of sphingomyelin to ceramide and phosphocholine. To address the related membrane dynamical structural changes and their feedback to enzyme activity, we have studied the effect of enzymatically generated ceramide in situ on the properties of a well-defined lipid model system. We found a gel-phase formation that was about four times faster than ceramide generation due to ceramide-sphingomyelin pairing. The gel-phase formation slowed down when the ceramide molar ratios exceeded those of sphingomyelin and stopped just at the solubility limit of ceramide, due to unfavorable pairwise interactions of ceramide with itself and with monounsaturated phosphatidylcholine. A remarkable correlation to in vitro experiments suggests a regulation of sphingomyelinase activity based on the sphingomyelin/ceramide molar ratio.

| S-EPMC2905085 | biostudies-literature

Lipid concentration and molar ratio boundaries for the use of isotropic bicelles.

Project description:Bicelles are model membranes generally made of long-chain dimyristoylphosphatidylcholine (DMPC) and short-chain dihexanoyl-PC (DHPC). They are extensively used in the study of membrane interactions and structure determination of membrane-associated peptides, since their composition and morphology mimic the widespread PC-rich natural eukaryotic membranes. At low DMPC/DHPC (q) molar ratios, fast-tumbling bicelles are formed in which the DMPC bilayer is stabilized by DHPC molecules in the high-curvature rim region. Experimental constraints imposed by techniques such as circular dichroism, dynamic light scattering, or microscopy may require the use of bicelles at high dilutions. Studies have shown that such conditions induce the formation of small aggregates and alter the lipid-to-detergent ratio of the bicelle assemblies. The objectives of this work were to determine the exact composition of those DMPC/DHPC isotropic bicelles and study the lipid miscibility. This was done using (31)P nuclear magnetic resonance (NMR) and exploring a wide range of lipid concentrations (2-400 mM) and q ratios (0.15-2). Our data demonstrate how dilution modifies the actual DMPC/DHPC molar ratio in the bicelles. Care must be taken for samples with a total lipid concentration ≤250 mM and especially at q ∼ 1.5-2, since moderate dilutions could lead to the formation of large and slow-tumbling lipid structures that could hinder the use of solution NMR methods, circular dichroism or dynamic light scattering studies. Our results, supported by infrared spectroscopy and molecular dynamics simulations, also show that phospholipids in bicelles are largely segregated only when q > 1. Boundaries are presented within which control of the bicelles' q ratio is possible. This work, thus, intends to guide the choice of q ratio and total phospholipid concentration when using isotropic bicelles.

| S-EPMC4072726 | biostudies-literature

Amyloid-?42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer's disease.

Project description:The relationship between amyloid-? (A?) species and tau pathology in Alzheimer's disease (AD) is not fully understood. Here, we provide direct evidence that A?42/40 ratio, not total A? level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid ? precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with A?42/40 ratio. Roles of A?42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential A?42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high A?42/40) cells, not with I47F cells (low A?42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the A?42/40 ratio in AD therapy.

| S-EPMC7070004 | biostudies-literature

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