Alzheimer’s disease, which is the most common form of dementia, is characterized by the aggregation of the amyloid β peptide (Aβ) and by an impairment of calcium homeostasis caused by excessive activation of glutamatergic receptors (excitotoxicity). Here, we studied the effects on calcium homeostasis caused by the formation of Aβ oligomeric assemblies. We found that Aβ oligomers cause a rapid influx of calcium ions (Ca2+) across the cell membrane by rapidly activating extrasynaptic N-methyl-D-aspartate (NMDA) receptors and, to a lower extent,α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) re-ceptors. We also observed, however, that misfolded oligomers do not interact directly with these receptors. Further experiments withlysophosphatidylcholine and arachidonic acid, which cause membrane compression and stretch, respectively, indicated that these receptors are activated through a change in membrane tension induced by the oligomers and transmitted mechanically to the receptors via the lipid bilayer. Indeed, lysophosphatidylcholine is able to neutralize the oligomer-induced activation of the NMDA receptors, whereas arachidonic acid activates the receptors similarly to the oligomers with no additive effects. An increased rotational freedom observed for a fluorescent probe embedded within the membrane in the presence of the oligomers also indicates a membrane stretch. These results reveal a mechanism of toxicity of Aβoligomers in Alzheimer’s disease through the perturbation of the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.

Aβ oligomers dysregulate calcium homeostasis by mechanosensitive activation of AMPA and NMDA receptors / Giulia Fani, Benedetta Mannini, Giulia Vecchi, Roberta Cascella, Cristina Cecchi, Christopher M. Dobson, Michele Vendruscolo, Fabrizio Chiti. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - ELETTRONICO. - 12:(2021), pp. 766-781. [10.1021/acschemneuro.0c00811]

Aβ oligomers dysregulate calcium homeostasis by mechanosensitive activation of AMPA and NMDA receptors.

Giulia Fani
Investigation
;
Benedetta Mannini
Investigation
;
Roberta Cascella
Investigation
;
Cristina Cecchi
Supervision
;
Fabrizio Chiti
Supervision
2021

Abstract

Alzheimer’s disease, which is the most common form of dementia, is characterized by the aggregation of the amyloid β peptide (Aβ) and by an impairment of calcium homeostasis caused by excessive activation of glutamatergic receptors (excitotoxicity). Here, we studied the effects on calcium homeostasis caused by the formation of Aβ oligomeric assemblies. We found that Aβ oligomers cause a rapid influx of calcium ions (Ca2+) across the cell membrane by rapidly activating extrasynaptic N-methyl-D-aspartate (NMDA) receptors and, to a lower extent,α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) re-ceptors. We also observed, however, that misfolded oligomers do not interact directly with these receptors. Further experiments withlysophosphatidylcholine and arachidonic acid, which cause membrane compression and stretch, respectively, indicated that these receptors are activated through a change in membrane tension induced by the oligomers and transmitted mechanically to the receptors via the lipid bilayer. Indeed, lysophosphatidylcholine is able to neutralize the oligomer-induced activation of the NMDA receptors, whereas arachidonic acid activates the receptors similarly to the oligomers with no additive effects. An increased rotational freedom observed for a fluorescent probe embedded within the membrane in the presence of the oligomers also indicates a membrane stretch. These results reveal a mechanism of toxicity of Aβoligomers in Alzheimer’s disease through the perturbation of the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.
12
766
781
Giulia Fani, Benedetta Mannini, Giulia Vecchi, Roberta Cascella, Cristina Cecchi, Christopher M. Dobson, Michele Vendruscolo, Fabrizio Chiti
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1235393
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