Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity.
Cells
; 8(8)2019 07 25.
Article
in En
| MEDLINE
| ID: mdl-31349637
ABSTRACT
Cholinergic dysfunction in Alzheimer's disease (AD) can be mediated by the neuronal α7 nicotinic acetylcholine receptor (α7nAChR). Beta-amyloid peptide (Aß) binds to the α7nAChR, disrupting the receptor's function and causing neurotoxicity. In vivo not only Aß but also its modified forms can drive AD pathogenesis. One of these forms, iso-Aß (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-Aß are α7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-Aß is a more potent inhibitor of the α7nAChR-mediated calcium current than unmodified Aß. However, Asp7 isomerization eliminated the ability of Aß to decrease the α7nAChR levels. These data indicate differences in the interaction of the peptides with the α7nAChR, which we demonstrated using computer modeling. Neither Aß nor iso-Aß competed with 125I-α-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-Aß was mediated by the α7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of Aß on the functional activity of the α7nAChR, which may be an important factor in the disruption of the cholinergic system in AD.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyloid beta-Peptides
/
Aspartic Acid
/
Alpha7 Nicotinic Acetylcholine Receptor
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cells
Year:
2019
Document type:
Article
Affiliation country:
RUSSIA