期刊
CELLS
卷 8, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/cells8080771
关键词
amyloid-beta; nicotinic acetylcholine receptor; modifications; Alzheimer's disease; neurotoxicity; calcium imaging; radioligand analysis; aspartate isomerization
类别
资金
- RUSSIAN SCIENCE FOUNDATION [19-74-30007]
- Russian Science Foundation [19-74-30007] Funding Source: Russian Science Foundation
Cholinergic dysfunction in Alzheimer's disease (AD) can be mediated by the neuronal alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR). Beta-amyloid peptide (A beta) binds to the alpha 7nAChR, disrupting the receptor's function and causing neurotoxicity. In vivo not only A beta but also its modified forms can drive AD pathogenesis. One of these forms, iso-A beta (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-A beta are alpha 7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-A beta is a more potent inhibitor of the alpha 7nAChR-mediated calcium current than unmodified A beta. However, Asp7 isomerization eliminated the ability of A beta to decrease the alpha 7nAChR levels. These data indicate differences in the interaction of the peptides with the alpha 7nAChR, which we demonstrated using computer modeling. Neither A beta nor iso-A beta competed with I-125-alpha-bungarotoxin for binding to the orthosteric site of the receptor, suggesting the allosteric binging mode of the peptides. Further we found that increased neurotoxicity of iso-A beta was mediated by the alpha 7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of A beta on the functional activity of the alpha 7nAChR, which may be an important factor in the disruption of the cholinergic system in AD.
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