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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 force measurements demonstrating theeffect of membrane-insertedAβpE3–42 oligomers on the mechanical propertiesof DOPS/POPE membranes. (A) Indentation curves (only approach is shown)for DOPS/POPE membranes without (blue) and with (red) inserted AβpE3–42 oligomers displaying the breakthrough forces(FB) and thicknesses (h) of the membranes. F is the force, and δis the tip–sample separation. (B) Histograms of breakthroughforces show FB1 = 1.31 ± 0.19 nNfor the DOPS/POPE membrane and FB2 = 1.83± 0.25 nN for a similar membrane with inserted AβpE3–42 oligomers. (C and D). Force maps of the analyzed data for (C) theDOPS/POPE membrane and (D) the DOPS/POPE membrane with inserted AβpE3–42 oligomers. The outline of the membrane patchis seen in panel D. An FB value of 0 wasgiven to curves that did not show breakthrough forces outside themembrane. These curves were not analyzed further. The peptide:lipidratio is 1:10 for all data.
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fig7: AFM force measurements demonstrating theeffect of membrane-insertedAβpE3–42 oligomers on the mechanical propertiesof DOPS/POPE membranes. (A) Indentation curves (only approach is shown)for DOPS/POPE membranes without (blue) and with (red) inserted AβpE3–42 oligomers displaying the breakthrough forces(FB) and thicknesses (h) of the membranes. F is the force, and δis the tip–sample separation. (B) Histograms of breakthroughforces show FB1 = 1.31 ± 0.19 nNfor the DOPS/POPE membrane and FB2 = 1.83± 0.25 nN for a similar membrane with inserted AβpE3–42 oligomers. (C and D). Force maps of the analyzed data for (C) theDOPS/POPE membrane and (D) the DOPS/POPE membrane with inserted AβpE3–42 oligomers. The outline of the membrane patchis seen in panel D. An FB value of 0 wasgiven to curves that did not show breakthrough forces outside themembrane. These curves were not analyzed further. The peptide:lipidratio is 1:10 for all data.

Mentions: We conducted force measurementson membrane patches with insertedAβpE3–42 oligomers. We characterized the mechanicalproperties of these membranes by measuring the breakthrough forceseen in indentation curves. These curves show that lipid membranesare first deformed elastically by the AFM tip (O–FB region in Figure 7A). At the critical breakthroughforce, marked by a discontinuity in the curve, the membrane undergoesan irreversible (plastic) deformation. The breakthrough force hasbeen characterized for different lipid membranes and found to be sensitiveto lipid composition, ionic strength, and temperature.61−70 We measured a value of 1.31 ± 0.22 nN (mean value ± thehalf-width at half-maximum) for the breakthrough force of DOPS/POPEmembranes. Insertion of AβpE3–42 oligomerssignificantly increased this value by ∼40% (Figure 7B–D).


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 force measurements demonstrating theeffect of membrane-insertedAβpE3–42 oligomers on the mechanical propertiesof DOPS/POPE membranes. (A) Indentation curves (only approach is shown)for DOPS/POPE membranes without (blue) and with (red) inserted AβpE3–42 oligomers displaying the breakthrough forces(FB) and thicknesses (h) of the membranes. F is the force, and δis the tip–sample separation. (B) Histograms of breakthroughforces show FB1 = 1.31 ± 0.19 nNfor the DOPS/POPE membrane and FB2 = 1.83± 0.25 nN for a similar membrane with inserted AβpE3–42 oligomers. (C and D). Force maps of the analyzed data for (C) theDOPS/POPE membrane and (D) the DOPS/POPE membrane with inserted AβpE3–42 oligomers. The outline of the membrane patchis seen in panel D. An FB value of 0 wasgiven to curves that did not show breakthrough forces outside themembrane. These curves were not analyzed further. The peptide:lipidratio is 1:10 for all data.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: AFM force measurements demonstrating theeffect of membrane-insertedAβpE3–42 oligomers on the mechanical propertiesof DOPS/POPE membranes. (A) Indentation curves (only approach is shown)for DOPS/POPE membranes without (blue) and with (red) inserted AβpE3–42 oligomers displaying the breakthrough forces(FB) and thicknesses (h) of the membranes. F is the force, and δis the tip–sample separation. (B) Histograms of breakthroughforces show FB1 = 1.31 ± 0.19 nNfor the DOPS/POPE membrane and FB2 = 1.83± 0.25 nN for a similar membrane with inserted AβpE3–42 oligomers. (C and D). Force maps of the analyzed data for (C) theDOPS/POPE membrane and (D) the DOPS/POPE membrane with inserted AβpE3–42 oligomers. The outline of the membrane patchis seen in panel D. An FB value of 0 wasgiven to curves that did not show breakthrough forces outside themembrane. These curves were not analyzed further. The peptide:lipidratio is 1:10 for all data.
Mentions: We conducted force measurementson membrane patches with insertedAβpE3–42 oligomers. We characterized the mechanicalproperties of these membranes by measuring the breakthrough forceseen in indentation curves. These curves show that lipid membranesare first deformed elastically by the AFM tip (O–FB region in Figure 7A). At the critical breakthroughforce, marked by a discontinuity in the curve, the membrane undergoesan irreversible (plastic) deformation. The breakthrough force hasbeen characterized for different lipid membranes and found to be sensitiveto lipid composition, ionic strength, and temperature.61−70 We measured a value of 1.31 ± 0.22 nN (mean value ± thehalf-width at half-maximum) for the breakthrough force of DOPS/POPEmembranes. Insertion of AβpE3–42 oligomerssignificantly increased this value by ∼40% (Figure 7B–D).

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