Small Liposomes Accelerate the Fibrillation of Amyloid β (1–40)

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Edited by Paul E. FraserThe aggregation of amyloid-␤ (A␤) on lipid bilayers has been implicated as a mechanism by which A␤ exerts its toxicity in Alzheimer's disease (AD). Lipid bilayer thinning has been observed during both oxidative stress and protein aggregation in AD, but whether these pathological modifications of the bilayer correlate with A␤ misfolding is unclear. Here, we studied peptide-lipid interactions in synthetic bilayers of the shortchain lipid dilauroyl phosphatidylcholine (DLPC) as a simplified model for diseased bilayers to determine their impact on A␤ aggregate, protofibril, and fibril formation. A␤ aggregation and fibril formation in membranes composed of dioleoyl phosphatidylcholine (DOPC) or 1-palmitoyl-2-oleoyl phosphatidylcholine mimicking normal bilayers served as controls. Differences in aggregate formation and stability were monitored by a combination of thioflavin-T fluorescence, circular dichroism, atomic force microscopy, transmission electron microscopy, and NMR. Despite the ability of all three lipid bilayers to catalyze aggregation, DLPC accelerates aggregation at much lower concentrations and prevents the fibrillation of A␤ at low micromolar concentrations. DLPC stabilized globular, membrane-associated oligomers, which could disrupt the bilayer integrity. DLPC bilayers also remodeled preformed amyloid fibrils into a pseudo-unfolded, molten globule state, which resembled on-pathway, protofibrillar aggregates. Whereas the stabilized, membrane-associated oligomers were found to be nontoxic, the remodeled species displayed toxicity similar to that of conventionally prepared aggregates. These results provide mechanistic insights into the roles that pathologically thin bilayers may play in A␤ aggregation on neuronal bilayers, and pathological lipid oxidation may contribute to A␤ misfolding.

Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Reduced Lipid Bilayer Thickness Regulates the Aggregation and Cytotoxicity of Amyloid-β

Korshavn

Satriano

Lin

et al. 2017

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158

“…1D, inset). Taken together, these results suggest that fibril formation by apoA-I 1-83/G26R on the SUV surface occurs by a different mechanism from that in bulk solution (35,36). Fig.…”

Section: Effects Of Membrane Binding On Fibril Formation Of Apoa-i 1-83mentioning

confidence: 51%

“…Membrane binding also increases the local concentration of proteins, and reduces the dimensionality of their collision via diffusion, promoting inter-molecular interaction and fibrillization (33,34). Most recently, lipid vesicles were shown to accelerate the nucleation step of ␣-synuclein (35) and amyloid-␤ peptide (36), triggering conversion into the aggregated state. Because apoA-I has a strong ability to bind to lipid membranes (37) and both the N-and C-terminal regions are involved in lipid binding (38), it is expected that membrane binding has a key role in the aggregation pathway of the N-terminal fragment of apoA-I.…”

mentioning

confidence: 99%

Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

Mizuguchi

Ogata

Mikawa

et al. 2015

Background:The N-terminal fragment of amyloidogenic apoA-I mutants deposits as fibrils by unknown mechanisms. Results: The G26R mutation partially prevents helix formation of the N-terminal fragment upon lipid binding, thereby facilitating ␤-transition and fibril formation. Conclusion: Membrane binding modulates fibril formation of apoA-I through partially destabilized helical conformation. Significance: The results reveal a new pathway for amyloid fibril formation by apoA-I.

“…This spontaneous conformational switch additionally points out that the C-terminal part of PB1-F2 is initially deprived of any secondary structure at these pH values. Indeed, whereas most ␣-helical proteins such as ␤ 2 -microglobulin, lysozyme, or prion protein need some chemical or thermal treatment to convert into amyloid structures in vitro (39 -41), natively disordered proteins as A␤, Shadoo, ␣-synuclain may switch to amyloid-like forms without recourse to denaturation treatment (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Amyloid Assemblies of Influenza A Virus PB1-F2 Protein Damage Membrane and Induce Cytotoxicity

Vidić

Richard

Péchoux

et al. 2016

PB1-F2 is a small accessory protein encoded by an alternative open reading frame in PB1 segments of most influenza A virus. PB1-F2 is involved in virulence by inducing mitochondria-mediated immune cells apoptosis, increasing inflammation, and enhancing predisposition to secondary bacterial infections. Using biophysical approaches we characterized membrane disruptive activity of the full-length PB1-F2 (90 amino acids), its N-terminal domain (52 amino acids), expressed by currently circulating H1N1 viruses, and its C-terminal domain (38 amino acids). Both full-length and N-terminal domain of PB1-F2 are soluble at pH values <6, whereas the C-terminal fragment was found soluble only at pH < 3. All three peptides are intrinsically disordered. At pH > 7, the C-terminal part of PB1-F2 spontaneously switches to amyloid oligomers, whereas full-length and the N-terminal domain of PB1-F2 aggregate to amorphous structures. When incubated with anionic liposomes at pH 5, full-length and the C-terminal part of PB1-F2 assemble into amyloid structures and disrupt membrane at nanomolar concentrations. PB1-F2 and its C-terminal exhibit no significant antimicrobial activity. When added in the culture medium of mammalian cells, PB1-F2 amorphous aggregates show no cytotoxicity, whereas PB1-F2 pre-assembled into amyloid oligomers or fragmented nanoscaled fibrils was highly cytotoxic. Furthermore, the formation of PB1-F2 amyloid oligomers in infected cells was directly reflected by membrane disruption and cell death as observed in U937 and A549 cells. Altogether our results demonstrate that membrane-lytic activity of PB1-F2 is closely linked to supramolecular organization of the protein.