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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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Schematics of supported membrane (SM) formation via proteoliposome(PL) rupture and fusion. (A) Aβ1–42 proteoliposomeshaving a very high concentration of membrane-inserted oligomers arenot able to form supported membranes by fusion of ruptured proteoliposomes.(B) AβpE3–42 proteoliposomes have lower concentrationsof inserted oligomers, thus being able to form supported membranes.The dimensions of the inserted and adsorbed AβpE3–42 oligomers are larger because of faster aggregation kinetics. Attractiveinteractions between Aβ1–42 and PE headgroupsinduce PE-rich proteoliposomes.
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fig8: Schematics of supported membrane (SM) formation via proteoliposome(PL) rupture and fusion. (A) Aβ1–42 proteoliposomeshaving a very high concentration of membrane-inserted oligomers arenot able to form supported membranes by fusion of ruptured proteoliposomes.(B) AβpE3–42 proteoliposomes have lower concentrationsof inserted oligomers, thus being able to form supported membranes.The dimensions of the inserted and adsorbed AβpE3–42 oligomers are larger because of faster aggregation kinetics. Attractiveinteractions between Aβ1–42 and PE headgroupsinduce PE-rich proteoliposomes.

Mentions: We found significantlylarger dimensions and lower densities formembrane-adsorbed and membrane-inserted AβpE3–42 oligomers than for Aβ1–42 oligomers (Figures 4 and 5 and Table 2). The larger size of AβpE3–42 oligomers is attributed to their faster kinetics of self-assembly(Figures 1 and 2). Thehigher density of Aβ1–42 oligomers appearsto be counterintuitive because of the repulsion expected between thenegatively charged Asp1 and Glu3 residues of Aβ1–42, with the also negatively charged PS headgroups in the membrane.However, this higher density of Aβ1–42 oligomersis understandable if we hypothesize that PE-reach domains are inducedby Aβ1–42 oligomers due to attractive charge–dipoleinteractions between the negatively charged residues and the zwitterionicPE headgroups (Figure 8), thus leading to formationof PE-rich proteoliposomes during lipid hydration in our proteoliposomepreparation protocol (method 1). In addition, the larger size of AβpE3–42 oligomers would increase the barrier for membraneinsertion leading to lower densities of inserted AβpE3–42 oligomers. However, once the peptide is inserted, the stronger interactionsof the more hydrophobic AβpE3–42 with thelipid tails would lead to a more stable conformation in the hydrophobiclipid core.


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)

Schematics of supported membrane (SM) formation via proteoliposome(PL) rupture and fusion. (A) Aβ1–42 proteoliposomeshaving a very high concentration of membrane-inserted oligomers arenot able to form supported membranes by fusion of ruptured proteoliposomes.(B) AβpE3–42 proteoliposomes have lower concentrationsof inserted oligomers, thus being able to form supported membranes.The dimensions of the inserted and adsorbed AβpE3–42 oligomers are larger because of faster aggregation kinetics. Attractiveinteractions between Aβ1–42 and PE headgroupsinduce PE-rich proteoliposomes.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Schematics of supported membrane (SM) formation via proteoliposome(PL) rupture and fusion. (A) Aβ1–42 proteoliposomeshaving a very high concentration of membrane-inserted oligomers arenot able to form supported membranes by fusion of ruptured proteoliposomes.(B) AβpE3–42 proteoliposomes have lower concentrationsof inserted oligomers, thus being able to form supported membranes.The dimensions of the inserted and adsorbed AβpE3–42 oligomers are larger because of faster aggregation kinetics. Attractiveinteractions between Aβ1–42 and PE headgroupsinduce PE-rich proteoliposomes.
Mentions: We found significantlylarger dimensions and lower densities formembrane-adsorbed and membrane-inserted AβpE3–42 oligomers than for Aβ1–42 oligomers (Figures 4 and 5 and Table 2). The larger size of AβpE3–42 oligomers is attributed to their faster kinetics of self-assembly(Figures 1 and 2). Thehigher density of Aβ1–42 oligomers appearsto be counterintuitive because of the repulsion expected between thenegatively charged Asp1 and Glu3 residues of Aβ1–42, with the also negatively charged PS headgroups in the membrane.However, this higher density of Aβ1–42 oligomersis understandable if we hypothesize that PE-reach domains are inducedby Aβ1–42 oligomers due to attractive charge–dipoleinteractions between the negatively charged residues and the zwitterionicPE headgroups (Figure 8), thus leading to formationof PE-rich proteoliposomes during lipid hydration in our proteoliposomepreparation protocol (method 1). In addition, the larger size of AβpE3–42 oligomers would increase the barrier for membraneinsertion leading to lower densities of inserted AβpE3–42 oligomers. However, once the peptide is inserted, the stronger interactionsof the more hydrophobic AβpE3–42 with thelipid tails would lead to a more stable conformation in the hydrophobiclipid core.

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