Autoinsertion of soluble oligomers of Alzheimer's Aβ(1–42) peptide into cholesterol-containing membranes is accompanied by relocation of the sterol towards the bilayer surface

BACKGROUND: Soluble Alzheimer's Aβ oligomers autoinsert into neuronal cell membranes, contributing to the pathology of Alzheimer's Disease (AD), and elevated serum cholesterol is a risk factor for AD, but the reason is unknown. We investigated potential connections between these two observations at the membrane level by testing the hypothesis that Aβ(1–42) relocates membrane cholesterol. RESULTS: Oligomers of Aβ(1–42), but not the monomeric peptide, inserted into cholesterol-containing phosphatidylcholine monolayers with an anomalously low molecular insertion area, suggesting concurrent lipid rearrangement. Membrane neutron diffraction, including isomorphous replacement of specific lipid hydrogens with highly-scattering deuterium, showed that Aβ(1–42) insertion was accompanied by outward displacement of membrane cholesterol, towards the polar surfaces of the bilayer. Changes in the generalised polarisation of laurdan confirmed that the structural changes were associated with a functional alteration in membrane lipid order. CONCLUSION: Cholesterol is known to regulate membrane lipid order, and this can affect a wide range of membrane mechanisms, including intercellular signalling. Previously unrecognised Aβ-dependent rearrangement of the membrane sterol could have an important role in AD

Concentration-independent spontaneously forming biomimetric vesicles

In this Letter we present small-angle neutron scattering data from a biomimetic system composed of the phospholipids dimyristoyl and dihexanoyl phosphorylcholine (DMPC and DHPC, respectively). Doping DMPC-DHPC multilamellar vesicles with either the negatively charged lipid dimyristoyl phosphorylglycerol (DMPG, net charge -1) or the divalent cation, calcium (Ca2+), leads to the spontaneous formation of energetically stabilized monodisperse unilamellar vesicles whose radii are concentration independent and in contrast with previous experimental observations

Neutron diffraction reveals sequence-specific membrane insertion of pre-fibrillar islet amyloid polypeptide and inhibition by rifampicin

AbstractHuman islet amyloid polypeptide (hIAPP) forms amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM). Pre-fibrillar hIAPP oligomers (in contrast to monomeric IAPP or mature fibrils) increase membrane permeability, suggesting an important role in the disease. In the first structural study of membrane-associated hIAPP, lamellar neutron diffraction shows that oligomeric hIAPP inserts into phospholipid bilayers, and extends across the membrane. Rifampicin, which inhibits hIAPP-induced membrane permeabilisation in functional studies, prevents membrane insertion. In contrast, rat IAPP (84% identical to hIAPP, but non-amyloidogenic) does not insert into bilayers. Our findings are consistent with the hypothesis that membrane-active pre-fibrillar hIAPP oligomers insert into beta cell membranes in NIDDM

Relationship between the unbinding and main transition temperatures of phospholipid bilayers under pressure

Using neutron diffraction and a specially constructed high pressure cell suitable for aligned multibilayer systems, we have studied, as a function of pressure, the much observed anomalous swelling regime in dimyristoyl- and dilauroyl-phosphatidylcholine bilayers, DMPC and DLPC, respectively. We have also reanalyzed data from a number of previously published experiments and have arrived at the following conclusions. (a) The power law behavior describing anomalous swelling is preserved in all PC bilayers up to a hydrostatic pressure of 240 MPa. (b) As a function of increasing pressure there is a concomitant decrease in the anomalous swelling of DMPC bilayers. (c) For PC lipids with hydrocarbon chains ≥13 carbons the theoretical unbinding transition temperature T* is coupled to the main gel-to-liquid crystalline transition temperature TM. (d) DLPC is intrinsically different from the other lipids studied in that its T* is not coupled to TM. (e) For DLPC bilayers we predict a hydrostatic pressure (>290MPa) where unbinding may occur

Minutes 1875

https://place.asburyseminary.edu/freemethodistminutesyearbooks/1013/thumbnail.jp

Minutes 1877

https://place.asburyseminary.edu/freemethodistminutesyearbooks/1015/thumbnail.jp

A swollen phase observed between the liquid-crystalline phase and the interdigitated phase induced by pressure and/or adding ethanol in DPPC aqueous solution

A swollen phase, in which the mean repeat distance of lipid bilayers is larger than the other phases, is found between the liquid-crystalline phase and the interdigitated gel phase in DPPC aqueous solution. Temperature, pressure and ethanol concentration dependences of the structure were investigated by small-angle neutron scattering, and a bending rigidity of lipid bilayers was by neutron spin echo. The nature of the swollen phase is similar to the anomalous swelling reported previously. However, the temperature dependence of the mean repeat distance and the bending rigidity of lipid bilayers are different. This phase could be a precursor to the interdigitated gel phase induced by pressure and/or adding ethanol.Comment: 7 pages, 6 figure

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure

Dynamic phase separation of fluid membranes with rigid inclusions

Membrane shape fluctuations induce attractive interactions between rigid inclusions. Previous analytical studies showed that the fluctuation-induced pair interactions are rather small compared to thermal energies, but also that multi-body interactions cannot be neglected. In this article, it is shown numerically that shape fluctuations indeed lead to the dynamic separation of the membrane into phases with different inclusion concentrations. The tendency of lateral phase separation strongly increases with the inclusion size. Large inclusions aggregate at very small inclusion concentrations and for relatively small values of the inclusions' elastic modulus.Comment: 6 pages, 6 figure

Inhibitors can arrest the membrane activity of human islet amyloid polypeptide independently of amyloid formation

AbstractHuman islet amyloid polypeptide (hIAPP), co-secreted with insulin from pancreatic β cells, misfolds to form amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM). Like many amyloidogenic proteins, hIAPP is membrane-active: this may be significant in the pathogenesis of NIDDM. Non-fibrillar hIAPP induces electrical and physical breakdown in planar lipid bilayers, and IAPP inserts spontaneously into lipid monolayers, markedly increasing their surface area and producing Brewster angle microscopy reflectance changes. Congo red inhibits these activities, and they are completely arrested by rifampicin, despite continued amyloid formation. Our results support the idea that non-fibrillar IAPP is membrane-active, and may have implications for therapy and for structural studies of membrane-active amyloid