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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 (A) height and (B) amplitude images of AβpE3–42 fibrils formed on a supported DOPS/POPE (1:1)lipid membrane afterincubation for 38 h at room temperature. Fibril structures on a seeminglyintact membrane are observed. The vertical color-coded scale is 25nm for panel A.
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fig3: AFM (A) height and (B) amplitude images of AβpE3–42 fibrils formed on a supported DOPS/POPE (1:1)lipid membrane afterincubation for 38 h at room temperature. Fibril structures on a seeminglyintact membrane are observed. The vertical color-coded scale is 25nm for panel A.

Mentions: We used AFM to characterize the morphology of Aβ oligomersadsorbed on anionic membranes and the loss of membrane integrity inducedby these oligomers. We attempted to monitor the adsorption of AβpE3–42 oligomers when they were allowed to interactwith preformed supported lipid bilayers. We did not observe oligomeradsorption even after incubation for several hours in the AFM liquidcell. Instead, fibrils were observed on membrane regions after ex situ incubation for 38 h (Figure 3). Significantly, membrane patches appeared to be intact withouta substantial number of adsorbed AβpE3–42 oligomersor apparent defects in the lipid bilayer. These results suggest weakinteractions between AβpE3–42 oligomers andheadgroups in the lipid membrane. In comparison, oligomeric and fibrillarself-assembled structures of full-length Aβs were found to formon different supported membranes.53−57


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 (A) height and (B) amplitude images of AβpE3–42 fibrils formed on a supported DOPS/POPE (1:1)lipid membrane afterincubation for 38 h at room temperature. Fibril structures on a seeminglyintact membrane are observed. The vertical color-coded scale is 25nm for panel A.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: AFM (A) height and (B) amplitude images of AβpE3–42 fibrils formed on a supported DOPS/POPE (1:1)lipid membrane afterincubation for 38 h at room temperature. Fibril structures on a seeminglyintact membrane are observed. The vertical color-coded scale is 25nm for panel A.
Mentions: We used AFM to characterize the morphology of Aβ oligomersadsorbed on anionic membranes and the loss of membrane integrity inducedby these oligomers. We attempted to monitor the adsorption of AβpE3–42 oligomers when they were allowed to interactwith preformed supported lipid bilayers. We did not observe oligomeradsorption even after incubation for several hours in the AFM liquidcell. Instead, fibrils were observed on membrane regions after ex situ incubation for 38 h (Figure 3). Significantly, membrane patches appeared to be intact withouta substantial number of adsorbed AβpE3–42 oligomersor apparent defects in the lipid bilayer. These results suggest weakinteractions between AβpE3–42 oligomers andheadgroups in the lipid membrane. In comparison, oligomeric and fibrillarself-assembled structures of full-length Aβs were found to formon different supported membranes.53−57

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