Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity

Crystal M. Vander Zanden; Lois Wampler; Isabella Bowers; Erik B. Watkins; Jaroslaw Majewski; Eva Y. Chi

doi:10.1021/acs.langmuir.9b02484

Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity

Crystal M. Vander Zanden
, Lois Wampler
, Isabella Bowers
, Erik B. Watkins
, Jaroslaw Majewski
, Eva Y. Chi

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

In Alzheimer's disease, the amyloid-beta peptide (Aβ) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aβ (Aβ_m) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aβ_m. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aβ_m, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aβ species were highly surface active and rapidly adopted β-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aβ species had affinity for the anionic membrane. Aβ_m rapidly converted to β-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aβ_m and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aβ toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. This work provides a structural understanding of Aβ neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer's disease and other neurodegenerative diseases.

Original language	English
Pages (from-to)	16024-16036
Number of pages	13
Journal	Langmuir
Volume	35
Issue number	48
DOIs	https://doi.org/10.1021/acs.langmuir.9b02484
State	Published - Dec 3 2019
Externally published	Yes

Funding

X-ray scattering experiments were performed at the Advanced Photon Source at Argonne National Laboratory using NSF’s ChemMatCARS Sector 15 beamline. NSF’s ChemMatCARS Sector 15 is supported by the Divisions of Chemistry (CHE) and Materials Research (DMR), National Science Foundation, under grant number NSF/CHE- 1834750. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. This work was supported by NSF grants 1150855 and 1605225 to E.Y.C. and a postdoctoral fellowship from ASERT IRACDA K12 GM088021 to C.M.V.Z. NSF provided support for J.M. to contribute to this project through their Independent Research and Development program. L.W. was a summer intern in the Undergraduate Pipeline Network (UPN) program supported by ASERT IRACDA K12 GM088021, UNMCCC P30 CA118100, UNM CTSC UL1 TR001449; and NM INBRE P20 GM103451. I.B. was supported by NSF award #1560058 as a summer intern for Research Experience for Undergraduates (REU) in Nano Science & Micro Systems. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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10.1021/acs.langmuir.9b02484

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title = "Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity",

abstract = "In Alzheimer's disease, the amyloid-beta peptide (Aβ) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aβ (Aβm) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aβm. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aβm, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aβ species were highly surface active and rapidly adopted β-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aβ species had affinity for the anionic membrane. Aβm rapidly converted to β-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aβm and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aβ toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. This work provides a structural understanding of Aβ neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer's disease and other neurodegenerative diseases.",

author = "\{Vander Zanden\}, \{Crystal M.\} and Lois Wampler and Isabella Bowers and Watkins, \{Erik B.\} and Jaroslaw Majewski and Chi, \{Eva Y.\}",

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doi = "10.1021/acs.langmuir.9b02484",

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AU - Vander Zanden, Crystal M.

AU - Wampler, Lois

AU - Bowers, Isabella

AU - Watkins, Erik B.

AU - Majewski, Jaroslaw

AU - Chi, Eva Y.

PY - 2019/12/3

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N2 - In Alzheimer's disease, the amyloid-beta peptide (Aβ) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aβ (Aβm) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aβm. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aβm, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aβ species were highly surface active and rapidly adopted β-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aβ species had affinity for the anionic membrane. Aβm rapidly converted to β-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aβm and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aβ toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. This work provides a structural understanding of Aβ neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer's disease and other neurodegenerative diseases.

AB - In Alzheimer's disease, the amyloid-beta peptide (Aβ) is implicated in neuronal toxicity via interactions with the cell membrane. Monomeric Aβ (Aβm) is intrinsically disordered, but it can adopt a range of aggregated conformations with varying toxicities from short fibrillar oligomers (FO), to globular nonfibrillar oligomers (NFO), and full-length amyloid fibrils. NFO is considered to be the most toxic, followed by fibrils, and finally Aβm. To elucidate molecular-level membrane interactions that contribute to their different toxicities, we used liquid surface X-ray scattering and Langmuir trough insertion assays to compare Aβm, FO, and NFO surface activities and interactions with anionic DMPG lipid monolayers at the air/water interface. All Aβ species were highly surface active and rapidly adopted β-sheet rich structures upon adsorption to the air/water interface. Likewise, all Aβ species had affinity for the anionic membrane. Aβm rapidly converted to β-sheet rich assemblies upon binding the membrane, and these aggregated structures of Aβm and FO disrupted hexagonally packed lipid domains and resulted in membrane thinning and instability. In contrast, NFO perturbed membrane structure by extracting lipids from the air/water interface and causing macroscale membrane deformations. Altogether, our results support two models for membrane-mediated Aβ toxicity: fibril-induced reorganization of lipid packing and NFO-induced membrane destabilization and lipid extraction. This work provides a structural understanding of Aβ neurotoxicity via membrane interactions and aids the effort in understanding early events in Alzheimer's disease and other neurodegenerative diseases.

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Fibrillar and Nonfibrillar Amyloid Beta Structures Drive Two Modes of Membrane-Mediated Toxicity

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