Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides

LASALA, M.; FABIANI, C.; CORRADI, J.; ANTOLLINI, S.S.; BOUZAT, C.

La Plata

Congreso; XLVII Renión Annual de la Sociedad Argentina de Biofísica; 2018

Sociedad Argentina de Biofísica

Amyloid β peptide (Aβ) is a key player in the development of Alzheimer disease(AD). It is the primary component of senile plaques in AD patients and is alsofound in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors hasbeen shown to be affected by Aβ soluble forms. To shed light into the molecularmechanism of this effect, we explored the direct actions of oligomeric Aβ1-40 andAβ1-42 on human α7 by fluorescence spectroscopy and single-channel recordings.Fluorescence measurements using the conformational sensitive probe crystalviolet (CrV), which shows different affinities for resting and desensitized states,revealed that Aβ induces α7 concentration-dependent conformational changes. At100 pM, Aβ displaces CrV Kd value for the resting state towards that of thedesensitized state from which α7 is still reactive to carbamycholine (Carb). Theseobservations are compatible with the induction of active/desensitized states aswell as of a novel conformational state in the presence of both Aβ and Carb. At100 nM Aβ, α7 adopts a resting-state-like structure which does not respond toCarb, indicating the stabilization of α7 in a blocked state. In real time, we foundthat Aβ is capable of eliciting α7 channel activity either in the absence or presenceof the positive allosteric modulator PNU-120596. Activation by Aβ is favored atpicomolar or low nanomolar concentrations and is not detected at micromolarconcentrations. At high Aβ concentrations, the durations of the activation episodeselicited by ACh are significantly reduced, an effect compatible with slow openchannelblock. We conclude that Aβ directly affects α7 function and acts as anagonist and a negative modulator: activation of α7 by low Aβ concentrations maybe involved in beneficial physiological effects, and the reduced α7 activity in thepresence of higher Aβ concentrations may contribute to the cholinergic signalingdeficit and may be involved in the initiation and development of AD.