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Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability.

Lee J, Gillman AL, Jang H, Ramachandran S, Kagan BL, Nussinov R, Teran Arce F - Biochemistry (2014)

Bottom Line: We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers.Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane.Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California at San Diego , La Jolla, California 92093, United States.

ABSTRACT
Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-β (Aβ) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Aβs, pyroglutamate (pE)-modified Aβ peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length Aβ1-40/42 peptides, these have not been sufficiently characterized for the more abundant AβpE3-42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AβpE3-42 and Aβ1-42 peptides. We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AβpE3-42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability.

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AFM images of (A) AβpE3–42 oligomers andmembrane defects induced by the oligomers in a DOPS/POPE (1:1) lipidbilayer and (B) Aβ1–42 oligomers adsorbedon a lipid bilayer with the same composition described above. (C)Aβ1–42 oligomers adsorbed on a lipid bilayerwith a lower peptide:lipid ratio. The peptide:lipid mass ratios are1:2 in panels A and B and 1:10 in panel C.
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fig4: AFM images of (A) AβpE3–42 oligomers andmembrane defects induced by the oligomers in a DOPS/POPE (1:1) lipidbilayer and (B) Aβ1–42 oligomers adsorbedon a lipid bilayer with the same composition described above. (C)Aβ1–42 oligomers adsorbed on a lipid bilayerwith a lower peptide:lipid ratio. The peptide:lipid mass ratios are1:2 in panels A and B and 1:10 in panel C.

Mentions: To increase the probabilityof Aβ peptides interacting withmembrane lipids, lipids were hydrated into liposomes in the presenceof peptides, subsequently sonicated together, and finally extrudedto form unilamellar proteoliposomes. Following this method, largequantities of AβpE3–42 oligomers adsorbedon a seemingly flat membrane were seen (Figure 4A). The adsorbed AβpE3–42 oligomers (greencircles) have typical diameters in the range of 30–40 nm andheights of 2–10 nm (Figures 4A and 5A,C and Table 2). In addition,bilayer deep (∼5 nm) gaps separating regions of seemingly intactpatches are observed. Smaller structures (≤2 nm in height)are found in these flatter regions, suggesting the presence of membrane-insertedoligomers. We compared the density and dimensions of adsorbed AβpE3–42 oligomers with those of Aβ1–42 oligomers. The Aβ1–42 oligomers have higherconcentrations (∼200 oligomers/μm) and smaller dimensionscompared to those of the AβpE3–42 oligomerseven though their heights are similar (Figures 4B and 5A,C and Table 2). In addition, a large surface density of membrane defects withdepths of one bilayer (dark spots) is observed. At lower peptide:lipidratios (Figure 4C), the number of these defectswas no longer significant and most of the observed structures protruded≤2 nm from the bilayer plane, suggesting a majority of insertedoligomers.


Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability.

Lee J, Gillman AL, Jang H, Ramachandran S, Kagan BL, Nussinov R, Teran Arce F - Biochemistry (2014)

AFM images of (A) AβpE3–42 oligomers andmembrane defects induced by the oligomers in a DOPS/POPE (1:1) lipidbilayer and (B) Aβ1–42 oligomers adsorbedon a lipid bilayer with the same composition described above. (C)Aβ1–42 oligomers adsorbed on a lipid bilayerwith a lower peptide:lipid ratio. The peptide:lipid mass ratios are1:2 in panels A and B and 1:10 in panel C.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4215883&req=5

fig4: AFM images of (A) AβpE3–42 oligomers andmembrane defects induced by the oligomers in a DOPS/POPE (1:1) lipidbilayer and (B) Aβ1–42 oligomers adsorbedon a lipid bilayer with the same composition described above. (C)Aβ1–42 oligomers adsorbed on a lipid bilayerwith a lower peptide:lipid ratio. The peptide:lipid mass ratios are1:2 in panels A and B and 1:10 in panel C.
Mentions: To increase the probabilityof Aβ peptides interacting withmembrane lipids, lipids were hydrated into liposomes in the presenceof peptides, subsequently sonicated together, and finally extrudedto form unilamellar proteoliposomes. Following this method, largequantities of AβpE3–42 oligomers adsorbedon a seemingly flat membrane were seen (Figure 4A). The adsorbed AβpE3–42 oligomers (greencircles) have typical diameters in the range of 30–40 nm andheights of 2–10 nm (Figures 4A and 5A,C and Table 2). In addition,bilayer deep (∼5 nm) gaps separating regions of seemingly intactpatches are observed. Smaller structures (≤2 nm in height)are found in these flatter regions, suggesting the presence of membrane-insertedoligomers. We compared the density and dimensions of adsorbed AβpE3–42 oligomers with those of Aβ1–42 oligomers. The Aβ1–42 oligomers have higherconcentrations (∼200 oligomers/μm) and smaller dimensionscompared to those of the AβpE3–42 oligomerseven though their heights are similar (Figures 4B and 5A,C and Table 2). In addition, a large surface density of membrane defects withdepths of one bilayer (dark spots) is observed. At lower peptide:lipidratios (Figure 4C), the number of these defectswas no longer significant and most of the observed structures protruded≤2 nm from the bilayer plane, suggesting a majority of insertedoligomers.

Bottom Line: We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers.Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane.Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California at San Diego , La Jolla, California 92093, United States.

ABSTRACT
Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-β (Aβ) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Aβs, pyroglutamate (pE)-modified Aβ peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length Aβ1-40/42 peptides, these have not been sufficiently characterized for the more abundant AβpE3-42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AβpE3-42 and Aβ1-42 peptides. We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AβpE3-42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability.

Show MeSH
Related in: MedlinePlus