Sugar distributions on gangliosides guide the formation and stability of amyloid-β oligomers

Saha, Jhinuk; Ford, Bradley; Wang, Xianjun; Boyd, Steven A.; Morgan, Sarah E.; Rangachari, Vijayaraghavan

doi:10.1016/j.bpc.2023.107073

Cited by 5 publications

(4 citation statements)

References 79 publications

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“…Previous work has measured a GM1 phase transition at a concentration in the range 10–100 μM that has been assigned to the critical micelle concentration (CMC) (Chakravorty et al, 2022 ; Oshima et al, 1993 ; Rauvala, 1979 ; Saha et al, 2023 ; Yohe & Rosenberg, 1972 ). However, these measurements relied on pyrene fluorescence or triiodide formation assays that report a change in the dielectric constant or hydrophobicity of the medium rather than a direct observation of micellar species and that can thus misrepresent the true CMC (Serravalle et al, 2024 ).…”

Section: Resultsmentioning

confidence: 99%

Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide

McCalpin,

Mechakra,

Ivanova

et al. 2024

Protein Science

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Despite causing over 1 million deaths annually, Type 2 Diabetes (T2D) currently has no curative treatments. Aggregation of the islet amyloid polypeptide (hIAPP) into amyloid plaques plays an important role in the pathophysiology of T2D and thus presents a target for therapeutic intervention. The mechanism by which hIAPP aggregates contribute to the development of T2D is unclear, but it is proposed to involve disruption of cellular membranes. However, nearly all research on hIAPP‐lipid interactions has focused on anionic phospholipids, which are primarily present in the cytosolic face of plasma membranes. We seek here to characterize the effects of three gangliosides, the dominant anionic lipids in the outer leaflet of the plasma membrane, on the aggregation, structure, and toxicity of hIAPP. Our results show a dual behavior that depends on the molar ratio between the gangliosides and hIAPP. For each ganglioside, a low‐lipid:peptide ratio enhances hIAPP aggregation and alters the morphology of hIAPP fibrils, while a high ratio eliminates aggregation and stabilizes an α‐helix‐rich hIAPP conformation. A more negative lipid charge more efficiently promotes aggregation, and a larger lipid headgroup improves inhibition of aggregation. hIAPP also alters the phase transitions of the lipids, favoring spherical micelles over larger tubular micelles. We discuss our results in the context of the available lipid surface area for hIAPP binding and speculate on a role for gangliosides in facilitating toxic hIAPP aggregation.

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Section: Resultsmentioning

confidence: 99%

Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide

McCalpin,

Mechakra,

Ivanova

et al. 2024

Protein Science

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“…Ahyayauch et al [ 18 ] showed that GM1 ganglioside was a major enhancer of Aβ binding to lipid bilayers in the L o state. In fact, gangliosides have repeatedly been described as promoting oligomer and fibril formation, in which their net negative charge is presumably involved [ 8 , 9 , 10 , 11 , 42 ]. The ganglioside effect may be non-linear with the dose.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Lipid Electric Charge on the Binding of Aβ(1–42) Amyloid Peptide to Bilayers in the Liquid-Ordered State

Ahyayauch,

Masserini,

Goñi

et al. 2024

Biomolecules

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The amyloidogenic Aβ peptides are widely considered as a pathogenic agent in Alzheimer’s disease. Aβ(1-42) would form aggregates of amyloid fibrils on the neuron plasma membranes, thus perturbing neuronal functionality. Conflicting data are available on the influence of bilayer order on Aβ(1-42) binding to membranes. In the present study, a biophysical approach was used in which isothermal calorimetry and surface pressure measurements were applied to explore the interaction of Aβ(1-42) in either monomeric, oligomeric, or fibrillar form with model membranes (bilayers or monolayers) in the liquid-ordered state that were either electrically neutral or negatively charged. In the latter case, this contained phosphatidic acid, cardiolipin, or ganglioside. The calorimetric studies showed that Aβ(1-42) fibrils, oligomers, and monomers could bind and/or be inserted into bilayers, irrespective of electric charge, in the liquid-ordered state, except that monomers could not interact with electrically neutral bilayers. The monolayer studies in the Langmuir balance demonstrated that Aβ(1-42) aggregation hindered peptide insertion into the monolayer, hindered insertion in the decreasing order of monomer > oligomer > fibril, and that lipid composition did not cause large differences in insertion, apart from a slight facilitation of monomer and oligomer insertion by gangliosides.

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“…These properties of Aβ have been shown to be associated with the pathogenesis of Alzheimer’s disease (AD). Studies have reported the aggregation-induced oligomer formation and membrane-disrupting properties of Aβ peptides [ 239 , 240 , 241 , 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 ]. Studies have also reported the interaction between beta-amyloid and LL-37 peptides [ 205 ].…”

Section: Influence Of Ll-37 On Amyloid Aggregationmentioning

confidence: 99%

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

Bhattacharjya,

Zhang,

Ramamoorthy

2024

Biomolecules

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Antimicrobial peptides (AMPs), as well as host defense peptides (HDPs), constitute the first line of defense as part of the innate immune system. Humans are known to express antimicrobial precursor proteins, which are further processed to generate AMPs, including several types of α/β defensins, histatins, and cathelicidin-derived AMPs like LL37. The broad-spectrum activity of AMPs is crucial to defend against infections caused by pathogenic bacteria, viruses, fungi, and parasites. The emergence of multi-drug resistant pathogenic bacteria is of global concern for public health. The prospects of targeting antibiotic-resistant strains of bacteria with AMPs are of high significance for developing new generations of antimicrobial agents. The 37-residue long LL37, the only cathelicidin family of AMP in humans, has been the major focus for the past few decades of research. The host defense activity of LL37 is likely underscored by its expression throughout the body, spanning from the epithelial cells of various organs—testis, skin, respiratory tract, and gastrointestinal tract—to immune cells. Remarkably, apart from canonical direct killing of pathogenic organisms, LL37 exerts several other host defense activities, including inflammatory response modulation, chemo-attraction, and wound healing and closure at the infected sites. In addition, LL37 and its derived peptides are bestowed with anti-cancer and anti-amyloidogenic properties. In this review article, we aim to develop integrative, mechanistic insight into LL37 and its derived peptides, based on the known biophysical, structural, and functional studies in recent years. We believe that this review will pave the way for future research on the structures, biochemical and biophysical properties, and design of novel LL37-based molecules.

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Sugar distributions on gangliosides guide the formation and stability of amyloid-β oligomers

Cited by 5 publications

References 79 publications

Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide

Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide

The Influence of Lipid Electric Charge on the Binding of Aβ(1–42) Amyloid Peptide to Bilayers in the Liquid-Ordered State

LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases

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