Limits...
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.

Show MeSH

Related in: MedlinePlus

(A) AFM imageof AβpE3–42 oligomers insertedinto a DOPS/POPE (1:1) membrane. A subpopulation of these oligomersforms pore structures. (B) Electrical recording data demonstratingthe activity induced by AβpE3–42 pore-formingoligomers. (C) Pore diameters estimated from eq 6 for the interval of single-pore conductances measured in our experiments(0–0.7 nS).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4215883&req=5

fig6: (A) AFM imageof AβpE3–42 oligomers insertedinto a DOPS/POPE (1:1) membrane. A subpopulation of these oligomersforms pore structures. (B) Electrical recording data demonstratingthe activity induced by AβpE3–42 pore-formingoligomers. (C) Pore diameters estimated from eq 6 for the interval of single-pore conductances measured in our experiments(0–0.7 nS).

Mentions: In addition to the adsorbed oligomers discussedabove, we observednumerous smaller structures protruding <2 nm from the membraneplane (red circles in Figures 4A,B). Thesestructures are attributed to populations of oligomers inserted intothe membrane. Similar to the membrane-adsorbed oligomers, the insertedAβ1–42 oligomers have higher concentrationsand smaller dimensions compared to those of the AβpE3–42 oligomers (Figures 4A,B and 5B,D and Table 2). Most of these oligomershave a globular appearance (Figure 6A), althougha smaller subpopulation of pore-forming oligomers was also found (inset).Their electrophysiological activity is indicated by discrete featuresin the ionic current passing through the lipid membrane (Figure 6B), with pore conductances of <0.7 nS.58 From these data, the pore diameters can be roughlyapproximated (Figure 6C) using eq 6:59,606with r is the pore radius, r0 = G/4σ, G is thesingle-pore conductance, σ is the solution conductivity(∼1.5 S/m for 150 mM KCl), and L is the porelength (∼6 nm). After longer recording times (∼20 minfollowing the first activity) and in approximately 50% of our experiments,an exponential-like phase was observed before the saturation currentof the amplifier was reached.58


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)

(A) AFM imageof AβpE3–42 oligomers insertedinto a DOPS/POPE (1:1) membrane. A subpopulation of these oligomersforms pore structures. (B) Electrical recording data demonstratingthe activity induced by AβpE3–42 pore-formingoligomers. (C) Pore diameters estimated from eq 6 for the interval of single-pore conductances measured in our experiments(0–0.7 nS).
© Copyright Policy
Related In: Results  -  Collection

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

fig6: (A) AFM imageof AβpE3–42 oligomers insertedinto a DOPS/POPE (1:1) membrane. A subpopulation of these oligomersforms pore structures. (B) Electrical recording data demonstratingthe activity induced by AβpE3–42 pore-formingoligomers. (C) Pore diameters estimated from eq 6 for the interval of single-pore conductances measured in our experiments(0–0.7 nS).
Mentions: In addition to the adsorbed oligomers discussedabove, we observednumerous smaller structures protruding <2 nm from the membraneplane (red circles in Figures 4A,B). Thesestructures are attributed to populations of oligomers inserted intothe membrane. Similar to the membrane-adsorbed oligomers, the insertedAβ1–42 oligomers have higher concentrationsand smaller dimensions compared to those of the AβpE3–42 oligomers (Figures 4A,B and 5B,D and Table 2). Most of these oligomershave a globular appearance (Figure 6A), althougha smaller subpopulation of pore-forming oligomers was also found (inset).Their electrophysiological activity is indicated by discrete featuresin the ionic current passing through the lipid membrane (Figure 6B), with pore conductances of <0.7 nS.58 From these data, the pore diameters can be roughlyapproximated (Figure 6C) using eq 6:59,606with r is the pore radius, r0 = G/4σ, G is thesingle-pore conductance, σ is the solution conductivity(∼1.5 S/m for 150 mM KCl), and L is the porelength (∼6 nm). After longer recording times (∼20 minfollowing the first activity) and in approximately 50% of our experiments,an exponential-like phase was observed before the saturation currentof the amplifier was reached.58

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