Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the ?7 Nicotinic Receptor and Promotes Neurotoxicity.

ABSTRACT: Cholinergic dysfunction in Alzheimer's disease (AD) can be mediated by the neuronal ?7 nicotinic acetylcholine receptor (?7nAChR). Beta-amyloid peptide (A?) binds to the ?7nAChR, disrupting the receptor's function and causing neurotoxicity. In vivo not only A? but also its modified forms can drive AD pathogenesis. One of these forms, iso-A? (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-A? are ?7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-A? is a more potent inhibitor of the ?7nAChR-mediated calcium current than unmodified A?. However, Asp7 isomerization eliminated the ability of A? to decrease the ?7nAChR levels. These data indicate differences in the interaction of the peptides with the ?7nAChR, which we demonstrated using computer modeling. Neither A? nor iso-A? competed with 125I-?-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? was mediated by the ?7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of A? on the functional activity of the ?7nAChR, which may be an important factor in the disruption of the cholinergic system in AD.

SUBMITTER: Barykin EP 

PROVIDER: S-EPMC6721525 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature