期刊
ACS CHEMICAL NEUROSCIENCE
卷 12, 期 4, 页码 766-781出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00811
关键词
Protein misfolding; neurodegenerative diseases; senile plaques; memantine; calcium homeostasis; membrane destabilization
资金
- Regione Toscana (FAS-Salute 2014), Project Supremal
- Progetto Dipartimento di Eccellenza Gender Medicine
- Fondi di Ateneo
Alzheimer's disease, the most common form of dementia, is characterized by the toxicity mechanism of Aβ oligomers through perturbing the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.
Alzheimer's disease, which is the most common form of dementia, is characterized by the aggregation of the amyloid beta peptide (A beta) 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 A beta oligomeric assemblies. We found that A beta 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, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We also observed, however, that misfolded oligomers do not interact directly with these receptors. Further experiments with lysophosphatidylcholine 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 A beta oligomers in Alzheimer's disease through the perturbation of the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.
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