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Preparation of Oligomeric β-amyloid1-42 and Induction of Synaptic Plasticity Impairment on Hippocampal Slices
Published on: July 14, 2010
Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons
Adam P Gunn1, Bruce X Wong1, Timothy Johanssen2
1From the Florey Institute of Neuroscience and Mental Health.
Abstract:
Pyroglutamate-modified amyloid-β (pE-Aβ) is a highly neurotoxic amyloid-β (Aβ) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of Aβ oligomerization and alters the interactions of Aβ with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aβ peptides has not been established. We report here that Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aβ(1-42)). In contrast, Aβ(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aβ3pE-42 did not. We also report that Aβ3pE-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. Aβ3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than Aβ(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of Aβ-dityrosine oligomer formation mediated by copper-redox cycling.
Insights
Pyroglutamate-amyloid-β (pE-Aβ) triggers neuronal membrane damage and lipid peroxidation, contributing to Alzheimer disease pathology. This neurotoxic Aβ isoform shows distinct interactions with neurons compared to standard Aβ.
Area of Science:
- Neuroscience
- Biochemistry
- Alzheimer Disease Research
Background:
- Pyroglutamate-modified amyloid-β (pE-Aβ) is a neurotoxic isoform found in Alzheimer disease (AD) brains.
- pE-Aβ formation accelerates amyloid-β (Aβ) oligomerization and alters interactions with copper and lipids, but its direct link to toxicity is unclear.
Purpose of the Study:
- To investigate the specific neurotoxic mechanisms of pE-Aβ, particularly the Aβ3pE-42 isoform.
- To compare the effects of Aβ3pE-42 with full-length Aβ(1-42) on primary cortical neurons.
Main Methods:
- Primary mouse cortical neurons were treated with Aβ3pE-42 and Aβ(1-42).
- Assays measured lipid peroxidation, reactive oxygen species (ROS) levels, calcium (Ca2+) influx, and membrane integrity.
- Neuronal binding of Aβ isoforms was assessed over time.
- Copper-mediated Aβ-dityrosine oligomerization was analyzed.
Main Results:
- Aβ3pE-42 significantly enhanced lipid peroxidation and triggered Ca2+ influx in neurons, unlike Aβ(1-42).
- Aβ3pE-42 preferentially bound to neuronal membranes, causing plasma membrane damage and remaining bound longer than Aβ(1-42).
- Pyroglutamate formation increased the efficiency of copper-redox cycling-mediated Aβ oligomerization.
Conclusions:
- Aβ3pE-42 exhibits distinct neurotoxic properties, including potent lipid peroxidation and membrane damage, contributing to Alzheimer disease pathogenesis.
- The enhanced membrane association and oligomerization of pE-Aβ are key factors in its increased neurotoxicity.
- Understanding pE-Aβ's mechanisms is crucial for developing targeted Alzheimer disease therapies.
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