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Pyroglutamylated amyloid beta peptides enhance non-fibrillogenic aggregation of the unmodified peptide

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Date Issued:
2016
Abstract/Description:
Alzheimer's disease (AD) is accompanied by abnormal extracellular deposition of amyloid b (Ab) peptide. This has led to the amyloid cascade hypothesis, causatively relating Ab with AD. While Ab deposits assume a fibrillar cross-b structure, prefibrillar oligomers of Ab have been identified as the main cytotoxic agents in AD. Pyroglutamylated amyloid beta (AbpE) peptides are N-terminally truncated and pyroglutamylated (at Glu3 or Glu11) Ab molecules that display enhanced cytotoxicity and represent up to 50% of total Ab in AD brains. AbpE significantly enhances the toxicity of unmodified Ab by an unknown mechanism. Although in situ Ab populations are heterogeneous, the majority of studies have been conducted on single Ab species. Here, we examined the structural and morphological changes that occur in mixed Ab/AbpE samples. Circular dichroism and transmission electron microscopy data indicate that AbpE3-42 forms b-sheet structure and undergoes delayed fibrillogenesis compared to unmodified Ab1-42. Further, AbpE3-42 decelerates b-sheet formation in mixed Ab1-42/AbpE3-42 samples. FTIR measurements, using 13C-labeled Ab1-42 and unlabeled AbpE3-42, indicate that AbpE3-42 inhibits cross-b-sheet formation by Ab1-42, which explains the retardation of fibrillogenesis. FTIR on peptides 13C-labeled at specific segments provided site specific structural information. Based on these data, the monomeric Ab structure has been modeled as a b-hairpin stabilized by intramolecular H-bonding with an N-terminal a-helix. These hairpins likely form higher order aggregates through ionic and hydrophobic interactions between the C-terminus of one hairpin and the N-terminus of another. Utilizing a novel technique, hydration from gas phase, we examined the a-helix to b-sheet transitions of these peptides. When combined, AbpE3-42 and Ab1-42 mutually inhibit intermolecular b-sheet formation, instead promoting formation of AbpE3-42/Ab1-42 hetero-oligomers of intramolecular H-bonding. These hetero-oligomers displayed enhanced toxicity to PC12 cells compared to individual peptides and induced greater calcium release from lipid vesicles than unmodified Ab. These results indicate that Ab and AbpE mutually inhibit fibrillogenesis and stabilize hetero-oligomers of enhanced cytotoxicity, possibly through a membrane permeabilization mechanism. Collectively, our findings lead to a new concept that Ab/AbpE hetero-oligomers, not just Ab or AbpE oligomers, are the main cytotoxic species in AD
Title: Pyroglutamylated amyloid beta peptides enhance non-fibrillogenic aggregation of the unmodified peptide.
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Name(s): Goldblatt, Gregory, Author
Tatulian, Suren, Committee Chair
Chen, Bo, Committee Member
Teter, Kenneth, Committee Member
King, Stephen, Committee Member
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2016
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Alzheimer's disease (AD) is accompanied by abnormal extracellular deposition of amyloid b (Ab) peptide. This has led to the amyloid cascade hypothesis, causatively relating Ab with AD. While Ab deposits assume a fibrillar cross-b structure, prefibrillar oligomers of Ab have been identified as the main cytotoxic agents in AD. Pyroglutamylated amyloid beta (AbpE) peptides are N-terminally truncated and pyroglutamylated (at Glu3 or Glu11) Ab molecules that display enhanced cytotoxicity and represent up to 50% of total Ab in AD brains. AbpE significantly enhances the toxicity of unmodified Ab by an unknown mechanism. Although in situ Ab populations are heterogeneous, the majority of studies have been conducted on single Ab species. Here, we examined the structural and morphological changes that occur in mixed Ab/AbpE samples. Circular dichroism and transmission electron microscopy data indicate that AbpE3-42 forms b-sheet structure and undergoes delayed fibrillogenesis compared to unmodified Ab1-42. Further, AbpE3-42 decelerates b-sheet formation in mixed Ab1-42/AbpE3-42 samples. FTIR measurements, using 13C-labeled Ab1-42 and unlabeled AbpE3-42, indicate that AbpE3-42 inhibits cross-b-sheet formation by Ab1-42, which explains the retardation of fibrillogenesis. FTIR on peptides 13C-labeled at specific segments provided site specific structural information. Based on these data, the monomeric Ab structure has been modeled as a b-hairpin stabilized by intramolecular H-bonding with an N-terminal a-helix. These hairpins likely form higher order aggregates through ionic and hydrophobic interactions between the C-terminus of one hairpin and the N-terminus of another. Utilizing a novel technique, hydration from gas phase, we examined the a-helix to b-sheet transitions of these peptides. When combined, AbpE3-42 and Ab1-42 mutually inhibit intermolecular b-sheet formation, instead promoting formation of AbpE3-42/Ab1-42 hetero-oligomers of intramolecular H-bonding. These hetero-oligomers displayed enhanced toxicity to PC12 cells compared to individual peptides and induced greater calcium release from lipid vesicles than unmodified Ab. These results indicate that Ab and AbpE mutually inhibit fibrillogenesis and stabilize hetero-oligomers of enhanced cytotoxicity, possibly through a membrane permeabilization mechanism. Collectively, our findings lead to a new concept that Ab/AbpE hetero-oligomers, not just Ab or AbpE oligomers, are the main cytotoxic species in AD
Identifier: CFE0006108 (IID), ucf:51195 (fedora)
Note(s): 2016-05-01
Ph.D.
Sciences, Biology
Doctoral
This record was generated from author submitted information.
Subject(s): amyloid beta -- Alzheimer's -- aggregation -- fibrillogenesis
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0006108
Restrictions on Access: public 2016-05-15
Host Institution: UCF

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