Role of the Fast Kinetics of Pyroglutamate-Modified Amyloid-β Oligomers in Membrane Binding and Membrane Permeability

Lee, Joon; Gillman, Alan L.; Jang, Hyunbum; Ramachandran, Srinivasan; Kagan, Bruce L.; Nussinov, Ruth; Arce, Fernando Terán

doi:10.1021/bi500587p

Cited by 33 publications

(57 citation statements)

References 94 publications

(167 reference statements)

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“…Additionally, we found that that the neuronal membrane damage caused by A␤3pE-42 results in a functional loss of plasma membrane integrity. These findings are consistent with recent publications demonstrating the capacity for A␤3pE-42 to form membrane-disrupting pores in synthetic lipid bilayers (22,23). Similarly, previous studies have shown that pE-A␤ oligomers disrupt lysosome membrane integrity in cultured neurons (50) and cause lactate dehydrogenase leakage from cultured astrocytes (49).…”

Section: Discussionsupporting

confidence: 92%

“…Neurons-Recent reports of pE-A␤ interactions with synthetic lipid membranes have suggested that pE-A␤ neurotoxicity is exerted via formation of ion-permeable membrane pores (22,23). We compared the capacity of A␤(1-42) and A␤3pE-42 to alter cellular ion homeostasis by measuring Ca 2ϩ flux in cortical neurons immediately following application of freshly prepared A␤.…”

Section: A␤3pe-42 Induces Rapid Ca 2ϩ Influx In Primary Corticalmentioning

confidence: 99%

“…pE-A␤ peptides also demonstrate increased ␤-sheet (aggregate structure) stability (16,17), differences in fibril ultrastructure (18,19), and altered interactions with copper ions (20,21) and synthetic lipid membranes (22,23). Notably, trace quantities of A␤3pE-42 have been observed to dramatically enhance the aggregation and neurotoxicity of A␤ (24), prompting descriptions of pE-A␤ as "prionlike."…”

mentioning

confidence: 99%

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Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Gunn

Wong

Johanssen³

et al. 2016

Journal of Biological Chemistry

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Pyroglutamate-modified amyloid-␤ (pE-A␤) is a highly neurotoxic amyloid-␤ (A␤) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of A␤ oligomerization and alters the interactions of A␤ with Cu 2؉ and lipids; however, a link between these properties and the toxicity of pE-A␤ peptides has not been established. We report here that A␤3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the fulllength isoform (A␤(1-42)). In contrast, A␤(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas A␤3pE-42 did not. We also report that A␤3pE-42 preferentially associates with neuronal membranes and triggers Ca 2؉ influx that can be partially blocked by the N-methyl-D-aspartate receptor antagonist MK-801. A␤3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than A␤(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of A␤-dityrosine oligomer formation mediated by copper-redox cycling.A␤ 3 peptides are found in every human brain; however, the concentration and composition of A␤ peptide isoforms are distinctly different in healthy individuals and people with AD (1-3). Amino-truncated A␤ peptides are abundant in the AD brain (4, 5) and increase in prevalence with disease progression (6). The process of A␤ amino-truncation can occur via the actions of aminopeptidases on full-length A␤ peptides (7, 8), via altered cleavage of amyloid precursor protein in the generation of A␤ (9 -11), and potentially by A␤-copper-redox cycling reactions (12). As a consequence, aminotruncation can expose glutamate residues (positions 3 and 11 of A␤) to cyclization by the action of glutaminyl cyclase (QC), forming the highly amyloidogenic pyroglutamate-A␤ (pE-A␤) peptides A␤3pE-40, A␤3pE-42, A␤11pE-40, and A␤11pE-42 (7, 13).Pyroglutamate formation significantly increases the hydrophobicity of A␤, causing the peptide to aggregate more rapidly and form oligomers at lower concentration thresholds (5, 14, 15). pE-A␤ peptides also demonstrate increased ␤-sheet (aggregate structure) stability (16, 17), differences in fibril ultrastructure (18,19), and altered interactions with copper ions (20, 21) and synthetic lipid membranes (22, 23). Notably, trace quantities of A␤3pE-42 have been observed to dramatically enhance the aggregation and neurotoxicity of A␤(1-42) (24), prompting descriptions of pE-A␤ as "prionlike." Still, it remains unclear as to the cytotoxic potency of pE-A␤ peptides compared with their full-length A␤ counterparts. Some studies have demonstrated pE-A␤ peptides to have enhanced toxicity (24 -26), although others have reported no difference in toxicity between the isoforms (27-30). Methodological differences may account somewhat for variability in the relative toxicities reported (Table 1), yet molecular mechanisms to explain...

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Section: Discussionsupporting

confidence: 92%

Section: A␤3pe-42 Induces Rapid Ca 2ϩ Influx In Primary Corticalmentioning

confidence: 99%

mentioning

confidence: 99%

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Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Gunn

Wong

Johanssen³

et al. 2016

Journal of Biological Chemistry

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“…Since proper membrane function requires balanced structural and mechanical properties, our AFM data provide additional perspective on how polyQ aggregates might hamper cellular activity. Our observation of the enhanced bilayer rigidity by polyQ adsorption and insertion is consistent with previous AFM force measurements, which showed that larger puncture forces are required for bilayers exposed to amyloid-β prefibrillar oligomers [21, 54]. Using an AFM mode referred to as the scanning probe acceleration microscopy (SPAM), Legleiter and coworkers measured the maximum tapping force (F max ) and minimal tapping force (F min ) of lipid bilayers during each tapping event [24, 25, 49, 55].…”

Section: Discussionsupporting

confidence: 91%

Polyglutamine aggregates impair lipid membrane integrity and enhance lipid membrane rigidity

Khadka

She

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Lipid membranes are suggested as the primary target of amyloid aggregates. We study aggregates formed by a polyglutamine (polyQ) peptide, and their disruptive effect on lipid membranes. Using solution atomic force microscopy (AFM), we observe polyQ oligomers coexisting with short fibrils, which have a twisted morphology that likely corresponds to two intertwined oligomer strings. Fourier transform infrared spectroscopy reveals that the content of β-sheet enriched aggregates increases with incubation time. Using fluorescence microscopy, we find that exposure to polyQ aggregates results in deflated morphology of giant unilamellar vesicles. PolyQ aggregates induced membrane disruption is further substantiated by time-dependent calcein leakage from the interior to the exterior of lipid vesicles. Detailed structural and mechanical perturbations of lipid membranes are revealed by solution AFM. We find that membrane disruption by polyQ aggregates proceeds by a two-step process, involving partial and full disruption. In addition to height contrast, the resulting partially and fully disrupted bilayers have distinct rigidity and adhesion force properties compared to the intact bilayer. Specifically, the bilayer rigidity increases as the intact bilayer becomes partially and fully disrupted. Surprisingly, the adhesion force first decreases and then increases during the disruption process. By resolving individual fibrils deposited on bilayer surface, we show that both the length and the number of fibrils can increase with incubation time. Our results highlight that membrane disruption could be the molecular basis of polyQ aggregates induced cytotoxicity.

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“…Atomic force microscopy (AFM) and Electron microscopy (EM) have been the most frequently utilized imaging techniques for examining the structure of Aβ pores in model membranes because of their highEresolution capabilities 9,19,20 . AFM images of Aβ oligomers reconstituted in model lipid bilayers show poreElike structures with outer pore diameters of 8E12 nm 21–23 . Electrical recording data obtained for various Aβ oligomers in suspended lipid membranes (also called black lipid membranes or BLM) display the heterogeneous multiple conductances characteristic of Aβ and all amyloid peptides studied to date 14,24 .…”

Section: Introductionmentioning

confidence: 99%

Amyloid β Ion Channels in a Membrane Comprising Brain Total Lipid Extracts

Lee¹,

Kim²,

Arce

et al. 2017

ACS Chem. Neurosci.

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Amyloid β (Aβ) oligomers are the predominant toxic species in the pathology of Alzheimer’s disease. The prevailing mechanism for toxicity by Aβ oligomers includes ionic homeostasis destabilization in neuronal cells by forming ion channels. These channel structures have been previously studied in model lipid bilayers. In order to gain further insight into the interaction of Aβ oligomers with natural membrane compositions, we have examined the structures and conductivities of Aβ oligomers in a membrane composed of brain total lipid extract (BTLE). We utilized two complementary techniques: atomic force microscopy (AFM) and black lipid membrane (BLM) electrical recording. Our results indicate that Aβ1–42 forms ion channel structures in BTLE membranes, accompanied by a heterogeneous population of ionic current fluctuations. Notably, the observed current events generated by Aβ1–42 peptides in BTLE membranes possess different characteristics compared to current events generated by the presence of Aβ1–42 in model membranes comprised of a 1:1 mixture of DOPS and POPE lipids. Oligomers of the truncated Aβ fragment Aβ17–42 (p3) exhibited similar ion conductivity behavior as Aβ1–42 in BTLE membranes. However, the observed macroscopic ion flux across the BTLE membranes induced by Aβ1–42 pores was larger than for p3 pores. Our analysis of structure and conductance of oligomeric Aβ pores in a natural lipid membrane closely mimics the in vivo cellular environment suggesting that Aβ pores could potentially accelerate the loss of ionic homeostasis and cellular abnormalities. Hence, these pore structures may serve as a target for drug development and therapeutic strategies for AD treatment.

show abstract

Role of the Fast Kinetics of Pyroglutamate-Modified Amyloid-β Oligomers in Membrane Binding and Membrane Permeability

Cited by 33 publications

References 94 publications

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Polyglutamine aggregates impair lipid membrane integrity and enhance lipid membrane rigidity

Amyloid β Ion Channels in a Membrane Comprising Brain Total Lipid Extracts

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