Molecular modulation of human alpha nicotinic receptor by amyloid-beta peptides

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

La Plata

Congreso; XLVII Reunión Anual de la Sociedad Argentina de Biofísica (SAB); 2018

Sociedad Argentina de Biofísica

Amyloid beta peptide (Ab) 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 alpha7 nicotinic receptors hasbeen shown to be affected by Ab soluble forms. To shed light into the molecularmechanism of this effect, we explored the direct actions of oligomeric Ab1-40 and Ab 1-42 on human alpha7 by fluorescence spectroscopy and single-channel recordings. Fluorescence  measurements  using  the  conformational  sensitive  probe  crystal violet  (CrV),  which  shows  different  affinities  for  resting  and  desensitized  states, revealed that Aβinduces α7 concentration-dependent conformational changes. At100  pM,  Ab displaces  CrV  Kd  value  for  the  resting  state  towards  that  of  thedesensitized state from which alpha7 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 Ab and Carb. At100  nM  Ab,  alpha7  adopts  a  resting-state-like  structure  which  does  not  respond  toCarb, indicating the stabilization of alpha7 in a blocked state. In real time, we foundthat Ab is capable of eliciting alpha7 channel activity either in the absence or presenceof  the  positive  allosteric  modulator  PNU-120596.  Activation  by  Ab is  favored  atpicomolar  or  low  nanomolar  concentrations  and  is  not  detected  at  micromolarconcentrations. At high Ab concentrations, the durations of the activation episodeselicited  by  ACh  are  significantly  reduced,  an  effect  compatible  with  slow  openchannel  block.  We  conclude  that  Ab directly  affects alpha7  function  and  acts  as  an agonist and a negative modulator: activation of alpha7 by low Ab concentrations maybe involved in beneficial physiological effects, and the reduced alpha7 activity in thepresence of higher Ab concentrations may contribute to the cholinergic signalingdeficit and may be involved in the initiation and development of AD.