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1. Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro

   https://doi.org/10.18632/aging.202138  

   Frankel, Daniel; Davies, Matthew; Bhushan, Bharat; Kulaberoglu, Yavuz; Urriola-Munoz, Paulina; Bertrand-Michel, Justine; Pergande, Melissa R.; Smith, Andrew A.; Preet, Swapan; Park, Thomas J.; et al (October 2020, Aging)

   null (Ed.)

   Naked mole-rats are extraordinarily long-lived rodents that offer unique opportunities to study the molecular origins of age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta (Aβ) peptide from a young age. Therefore, they represent a particularly favourable organism to study the mechanisms of resistance against Aβ neurotoxicity. Here we examine the composition, phase behaviour, and Aβ interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with the metabolism of ceramides, sphingomyelins and sphingosine-1-phosphate receptor 1 were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase extending to 80% of the supported lipid bilayer. These observations are consistent with the ‘membrane pacemaker’ hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. We also found that exposure to Aβ disrupts naked mole-rat brain lipid membranes significantly, breaking the membrane into pieces while mouse brain derived lipids remain largely intact upon Aβ exposure. 

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2. Micron-scale, liquid-liquid phase separation in ternary lipid membranes containing DPPE

   https://doi.org/10.1101/2025.05.08.652930  

   Goetz, Gunnar J; Naomi, Sasha; Madrigal, Angelique M; Chang, Catherine LA; Cornell, Caitlin E; Keller, Sarah L (May 2025, bioRxiv)

   Micron-scale, liquid-liquid phase separation occurs in membranes of living cells, with physiological consequences. To discover which lipids might support phase separation in cell membranes and how lipids might partition between phases, miscibility phase diagrams have been mapped for model membranes. Typically, model membranes are composed of ternary mixtures of a lipid with a high melting temperature, a lipid with a low melting temperature, and cholesterol. Phospholipids in ternary mixtures are chosen primarily to favor stable membranes (phosphatidylcholines and sphingomyelins) or add charge (phosphatidylglycerols and phosphatidylserines). A major class of phospholipids missing from experimental ternary diagrams has been the phosphatidylethanolamines (PEs). PE-lipids constitute up to 20 mol% of common biological membranes, where they influence protein function and facilitate membrane fusion. These biological effects are often attributed to PE’s smaller headgroup, which leads to higher monolayer spontaneous curvatures and higher melting temperatures. Taken alone, the higher melting points of saturated PE-lipids imply that liquid-liquid phase separation should persist to higher temperatures in membranes containing PE-lipids. Here, we tested that hypothesis by substituting a saturated PE-lipid (DPPE) for its corresponding PC-lipid (DPPC) in two well-studied ternary membranes (DOPC/DPPC/cholesterol and DiphyPC/DPPC/cholesterol). We used fluorescence microscopy to map full ternary phase diagrams for giant vesicles over a range of temperatures. Surprisingly, we found no micron-scale, liquid-liquid phase separation in vesicles of the first mixture (DOPC/DPPE/cholesterol), and only a small region of liquid-liquid phase separation in the second mixture (DiphyPC/DPPE/cholesterol). Instead, coexisting solid and liquid phases were widespread, with the solid phase enriched in DPPE. An unusual feature of these ternary membranes is that solid and liquid-ordered phases can be distinguished by fluorescence microscopy, so tie-line directions can be estimated throughout the phase diagram, and transition temperatures to the 3-phase region (containing a liquid-disordered phase, a liquid-ordered phase, and a solid phase) can be accurately measured. 

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3. Raft-like lipid mixtures in the highly coarse-grained Cooke membrane model

   https://doi.org/10.1063/5.0230727  

   Varma, Malavika; Khuri-Makdisi, Farid; Deserno, Markus (September 2024, The Journal of Chemical Physics)

   Lipid rafts are nanoscopic assemblies of sphingolipids, cholesterol, and specific membrane proteins. They are believed to underlie the experimentally observed lateral heterogeneity of eukaryotic plasma membranes and implicated in many cellular processes, such as signaling and trafficking. Ternary model membranes consisting of saturated lipids, unsaturated lipids, and cholesterol are common proxies because they exhibit phase coexistence between a liquid-ordered (lo) and liquid-disordered (ld) phase and an associated critical point. However, plasma membranes are also asymmetric in terms of lipid type, lipid abundance, leaflet tension, and corresponding cholesterol distribution, suggesting that rafts cannot be examined separately from questions about elasticity, curvature torques, and internal mechanical stresses. Unfortunately, it is challenging to capture this wide range of physical phenomenology in a single model that can access sufficiently long length- and time scales. Here we extend the highly coarse-grained Cooke model for lipids, which has been extensively characterized on the curvature-elastic front, to also represent raft-like lo/ld mixing thermodynamics. In particular, we capture the shape and tie lines of a coexistence region that narrows upon cholesterol addition, terminates at a critical point, and has coexisting phases that reflect key differences in membrane order and lipid packing. We furthermore examine elasticity and lipid diffusion for both phase separated and pure systems and how they change upon the addition of cholesterol. We anticipate that this model will enable significant insight into lo/ld phase separation and the associated question of lipid rafts for membranes that have compositionally distinct leaflets that are likely under differential stress—like the plasma membrane. 

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4. Dipolar Janus liposomes: formation, electrokinetic motion and self-assembly

   https://doi.org/10.1039/c9sm02254f  

   Liu, Zening; Cui, Jinyan; Zhan, Wei (March 2020, Soft Matter)

   Presented herein is the first report on dipolar Janus liposomes–liposomes that contain opposite surface charges decorating the two hemispheres of the same colloidal body. Such heterogeneous organization of surface charge is achieved through cholesterol-modulated lipid phase separation, which sorts anionic/cationic lipids into coexisting liquid-ordered/liquid-disordered domains. We present optimized experimental conditions to produce these liposomes in high yields, based on the gel-assisted hydration of ternary lipid systems consisting of cholesterol, 1,2-dipalmitoyl- sn-glycero -3-phosphocholine, and 1,2-dioleoyl- sn-glycero -3-phosphocholine. The size/charge distribution and domain configuration of these liposomes are characterized in detail by confocal fluorescence microscopy, nanosphere binding and zeta potential measurements. Using confocal fluorescence microscopy, we also follow the electrokinetic motion as well as the electrostatic self-assembly of these new dipolar Janus particles. 

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5. Interdependence of cholesterol distribution and conformational order in lipid bilayers

   https://doi.org/10.1116/6.0002489  

   Aghaaminiha, Mohammadreza; Farnoud, Amir M.; Sharma, Sumit (May 2023, Biointerphases)

   We show, via molecular simulations, that not only does cholesterol induce a lipid order, but the lipid order also enhances cholesterol localization within the lipid leaflets. Therefore, there is a strong interdependence between these two phenomena. In the ordered phase, cholesterol molecules are predominantly present in the bilayer leaflets and orient themselves parallel to the bilayer normal. In the disordered phase, cholesterol molecules are mainly present near the center of the bilayer at the midplane region and are oriented orthogonal to the bilayer normal. At the melting temperature of the lipid bilayers, cholesterol concentration in the leaflets and the bilayer midplane is equal. This result suggests that the localization of cholesterol in the lipid bilayers is mainly dictated by the degree of ordering of the lipid bilayer. We validate our findings on 18 different lipid bilayer systems, obtained from three different phospholipid bilayers with varying concentrations of cholesterol. To cover a large temperature range in simulations, we employ the Dry Martini force field. We demonstrate that the Dry and the Wet Martini (with polarizable water) force fields produce comparable results. 

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